Case study 25.1
A 35-year-old, otherwise healthy woman presents with thrombocytosis, ranging from 495 × 109/L to 600 × 109/L, which is reproducibly detected in several complete blood counts (CBCs) performed over the last 3 years. Possible causes of reactive thrombocytosis were excluded, and the referring physician favored a diagnosis of essential thrombocythemia (ET).
1. Should the patient perform additional tests?
- No, the diagnosis can be made as such, considering the exclusion of reactive causes and the persistence of thrombocytosis over the past 3 years
- Yes, additional tests are needed before we can conclude that this is essential thrombocythemia
The revised 2008 World Health Organization (WHO) criteria for the diagnosis of ET require all of the following: (i) a confirmed platelet count >450 × 109/L; (ii) results of bone marrow biopsy showing normal or slightly reduced cellularity with no or little granulocyte or erythroid proliferation, accompanied by marked proliferation of large and mature-appearing megakaryocytes; (iii) exclusion of other myeloid disorders mimicking ET, including chronic myelogenous leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), and some myelodysplastic syndromes (MDS); and (iv) demonstration of the JAK2V617 mutation or any other clonal marker, or, in the absence of a clonal marker, no evidence of reactive thrombocytosis. Therefore, we would recommend that this subject undergoes bone marrow biopsy and mutational analysis for JAK2V617F, bearing in mind that up to 40% of ET patients may be lacking the mutation. In specialized laboratories, mutations in the thrombopoietin receptor gene MPL (particularly at codon 515) can also be searched for; MPL mutations account for about 5% of ET patients without the JAK2V617F abnormality.
In 2013, mutations in the calreticulin (CALR) gene were discovered in 60–80% of patients with JAK2V617F and MPL unmutated patients (Klampfl et al.; Nangalia et al.) accounting for 15–25% of all patients with essential thrombocytosis. Therefore, search for CALR mutations represents a second line molecular test to be order in the JAK2V617F mutation test is negative in the diagnostic process for suspected thrombocytosis.
My patient, as above, performed bone marrow biopsy and the JAK2V617F mutation analysis; the latter was ranked as “positive” from the reference laboratory. However, I am aware that other laboratories also perform a quantitative analysis of the amount of mutated alleles (expressed as the ratio of mutated to wild-type alleles).
2. Do I need to perform this measurement in any patient with ET?
- No
- Yes
At present, there is no obvious clinical impact of measuring the JAK2V617F allele burden outside a clinical study. Usually, patients with ET have an allele burden in the lowest quartile (as opposed to patients with PV and PMF, in whom the median allele burden is in the second to fourth quartile), but this cannot be used as a criterion for differential diagnosis among the three classic MPNs, due to their significant overlapping. Furthermore, although several studies, including three meta-analyses, have shown that JAK2V617F-mutated ET patients are more prone to arterial and venous thrombosis than those with the wild-type counterpart, positivity for the JAK2V617F mutation is not (yet) accepted as a criterion for definition of “high-risk disease” and, consequently, for adjusting therapeutic management. Finally, although a higher allelic burden and/or its progressive increase have been associated with transformation to post-ET myelofibrosis, there is currently no recommendation to monitor changes in JAK2V617F allelic burden over time.
17: Management of Therapy-Related Myeloid Neoplasms
11: Minimal Residual Disease in Acute Myeloid Leukemia
71: Secondary Brain and Spinal Cord Tumors
