An 80-year old male presents with longstanding monocytosis and progressive thrombocytosis without anemia (Hb = 13.4 g/dL; Hct = 41.3%; WBC 5.9 × 109/L [monocytes 1.42 × 109/L, 24%]; Plt = 1.348 × 109/L). Epo levels are within normal limits, while LDH levels are increased (290 U/L; range: 135–225). Morphologic assessment of a BM smear is not informative due to absent cellularity, whereas a BM biopsy (d–f) features hypercellularity with increased myeloid-to-erythroid ratio, myeloid left shifting, and a well-represented CD14+ monocyte component. The megakaryocytes display clustering with frequent giant hyperlobated forms. Small megakaryocytes with maturation defects are also present. Reticulin stain and blast count are unremarkable. Targeted next generation sequencing (NGS) on the peripheral blood cells documents mutations of TET2 (VAF = 37%), JAK2 (VAF = 26%) and CALR (VAF = 28%); the karyotype is normal.The clinic-pathologic picture is consistent with a myeloid neoplasm with monocytosis and poses the differential diagnosis between PMF and chronic myelomonocytic leukemia. While the overall histological picture is more in keeping with MPN, the left shifting of the myeloid series and the maturation defects of the megakaryocytes may, in contrast, suggest multi-lineage dysplasia. However, the mutational profile favors a JAK2/CALR-driven MPN. TET2 mutations are of little value, as they can be present (likely as early clonal events) both in MPN, MDS/MPN, and in clonal hematopoiesis of indeterminate potential (CHIP) [,,,,]. As to the unusual coexistence of driver gene mutations, a JAK2/CALR double-mutated genotype has been reported rarely in MPNs and does not correlate with specific clinical phenotypes [,]. Finally, it should be stressed that monocytosis in MPNs is mostly observed alongside fibrotic progression and may be assumed as an indicator of accelerated phase disease [,]. This was not the case for our patient.
A 41-year old male presents with a 5-year history of erythrocytosis and high hematocrit levels. Laboratory test at presentation disclose high Hb (17.8 g/dL) and Hct (54%), normal WBC (6.7 × 109/L) and platelet counts (203 × 109/L), and erythropoietin (Epo) levels below local laboratory ranges (3.9 mU/mL [4.3–29]). A JAK2 mutation with 2.8% variant allele frequency (VAF) is detected on peripheral blood granulocytes (data on exon 12 and/or additional exon 14 mutations not available). The overall clinical presentation is suspected for PV and prompts a BM evaluation. A BM biopsy () features cellularity within age-related limits, preserved maturation of erythroid and myeloid lineages, and only a minor increase in megakaryocytes. The latter are sparse in distribution, with predominant mature-type morphology and only rare, scattered large forms. Thus, the lack of clear-cut major criterion 2 () does not allow a diagnosis of PV and warrants a provisional characterization as MPN-U.\nIn the present case, the histology is not inconsistent with the clinical diagnosis of PV, but it is not robust (particularly, some clustering of megakaryocytes with scattered large forms are disputable). A pre-morphologic diagnosis of MPN (i.e., a diagnosis made without full-blown MPN histology) is not common []. Indeed, it may occur in clinical settings where awareness of early phase MPNs suggests comprehensive laboratory and molecular screening, including quantitative PCR for low-burden driver gene mutations []. In such a context, it is worth noting that low VAF of JAK2 may be due to multiple base mutations in exon 14, which may hamper primer annealing and affect the quantification of the mutational burden []. Thus, searching for additional exon 14 mutations may be justified in cases with inexplicably low burdens of JAK2.