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JCP Online First, published on August 7, 2012 as 10.1136/jclinpath-2012-201008 PostScript CORRESPONDENCE
Referral centre variation in requesting JAK2 V617F mutation analysis for the investigation of a myeloproliferative neoplasm The discovery of the JAK2 V617F mutation has undoubtedly revolutionised the diagnosis of the classical Philadelphia chromosomenegative myeloproliferative neoplasms (MPNs) with the mutation present in greater than 95% of polycythaemia vera (PV) patients, approximately 50% of patients with essential thrombocythaemia (ET) and primary myelofibrosis (PMF) and, to a lesser degree, in a number of other myeloid malignancies such as refractory anaemia with ringed sideroblasts with thrombocytosis, chronic myelomonocytic leukaemia and acute myeloid leukaemia. Detection of this mutation is beneficial in differentiating between a reactive haematological response and a true clonal disorder and can also serve as a target for therapeutic intervention.1 Current guidelines for the diagnosis of PV, ET and PMF maintain the requirement for inclusion and/or exclusion of numerous other clinical and laboratory parameters such as histopathological examination of a bone marrow biopsy.2–4 Molecular testing for the presence of the JAK2 V617F mutation is now not only used for confirmation of MPN diagnosis, but has become insidiously perceived as a frontline test for the investigation of a neutrophilia, thrombocytosis or erythrocytosis, all relatively common haematological abnormalities.5 While numerous studies have addressed the technical aspects of JAK2 V617F mutation identification and allele burden estimation, limited information is available on the referral centre criteria for molecular testing and the reproducibility of application of these criteria. To address these issues, an audit was performed on 7005 diagnostic JAK2 V617F requests between January 2006 and April 2012 inclusive, received at a de facto
national centre for molecular testing of haematological malignancies that serves a population of over 4.2 million inhabitants. Assumptions are that within the population studied, no geographical differences exist in the frequency of JAK2 V617F-positive MPNs and that the annual incidence of JAK2 V617F-positive MPNs remains constant. A year-upon-year increase in the number of requests was observed despite the number of newly diagnosed JAK2 V617F patients remaining relatively constant for the audit period covered (figure 1). This implies a continual relaxation in the application of requesting criteria across all referral centres, but may also reflect an increasing knowledge of test availability. Further analysis was limited to those centres referring greater than 10 requests per annum (n=22) resulting in a final evaluation of 6600 test requests, of which 10 centres accounted for greater than 75% of tests. Conspicuously, a wide range in the individual referral centre JAK2 V617F ‘hit-rate’ was evident (range 8.5–38.8%, median 21.8%), suggesting no national consensus approach to JAK2 V617F testing. Provision of relevant clinical details on request forms also varied significantly from centre to centre (range 20.4–91.4%, median 66.3%). Of those requests where the only clinical details provided were either erythrocytosis, elevated haemoglobin and/or raised haematocrit, 15.2% harboured JAK2 V617F; of those requests where the sole clinical details were given as thrombocytosis, only 14.4% possessed JAK2 V617F; and of those requests where the clinical details indicated leucocytosis or neutrophilia, 17.2% were found to possess the JAK2 V617F mutation. Indications for JAK2 V617F screening appear to vary by referral centre, and most likely from physician to physician, and can be attributed to ambiguity in certain clinical scenarios, for example, should all patients with venous or arterial thrombosis be screened or just those presenting with splanchnic vein thrombosis?6 Completing the request form with appropriate clinical details is essential for appropriate diagnostic testing and also to
instigate rational, reflexive testing for other less frequent mutations associated with MPNs, for example, JAK2 exon 12 mutations, MPL exon 10 mutations that would aid in a composite diagnosis. Findings have been disseminated to all referral centres with further audits scheduled to identify barriers that prohibit the translation of diagnostic recommendations into practice and to reassess requesting patterns. This brief but informative audit highlights the difficulties in implementing diagnostic guidelines, acknowledged to influence subsequent treatment approaches,7 and emphasises the need for education and adoption of consensus guidelines for the systematic investigation of a neutrophilia, erythrocytosis, thrombocytosis or confirmation of a suspected MPN. In turn, this targeted rather than diffuse approach should optimise the use of valuable laboratory resources. Stephen E Langabeer Cancer Molecular Diagnostics, Central Pathology Laboratory, St James’s Hospital, Dublin, Republic of Ireland Correspondence to Dr Stephen E Langabeer, Cancer Molecular Diagnostics, Central Pathology Laboratory, St James’s Hospital, Dublin 8, Republic of Ireland;
[email protected] Acknowledgements The author acknowledges the contributions of Semsa Alibasic, Penny Clarke, Mireille Crampe, Sarah Daly, Tara Durney, Karl Haslam, Sarah McCarron, Niamh McCarthy, Karen Molloy and Fiona Quinn to this work. Contributors This manuscript is the sole work of the author. Competing interests None declared. Ethics approval Review from central laboratory testing. Ethics committee approval required from referral centres. Provenance and peer review Not commissioned; externally peer reviewed. J Clin Pathol 2012;0:1. doi:10.1136/jclinpath-2012-201008
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Figure 1 Annual frequency of JAK2 V617F requests received. Solid bars: JAK2 V617F-positive patients; *expected frequency extrapolated from data for the first 4 months of 2012. J Clin Pathol Month Article 2012 Vol 0 author No 0 Copyright
Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 2011;29:573–82. McMullin MF, Reilly JT, Campbell P, et al. Amendment to the guideline for the diagnosis and investigation of polycythaemia/erythrocytosis. Br J Haematol 2007;138:821–2. Swerdlow SH, Campo E, Lee Harris N, et al., eds. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC, 2008. Harrison CN, Bareford D, Butt N, et al. Guideline for the investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 2010;149:353–75. Tefferi A, Noel P, Hanson CA. Uses and abuses of JAK2 and MPL mutation tests in myeloproliferative neoplasms: a paper from the 2010 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn 2011;13:461–6. Xavier SG, Gadhela T, Rezende SM, et al. JAK2 V617F mutation in patients with thrombosis: to screen or not to screen? Int J Lab Hematol 2011;33:117–24. Peterson EA, Zypchen L, Lee VH, et al. Published guidelines versus real-life practice in the diagnosis and treatment of essential thrombocythemia. Am J Hematol 2011;89:792–4.
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Referral centre variation in requesting JAK2 V617F mutation analysis for the investigation of a myeloproliferative neoplasm Stephen E Langabeer J Clin Pathol published online August 7, 2012
doi: 10.1136/jclinpath-2012-201008
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