A 32-year old male with unremarkable past clinical history presents with persistent thrombocytosis (Hb = 15.6 g/dL; Hct = 46.1%; WBC = 6.76 × 109/L; Plt = 745 × 109/L; Epo and LDH levels within normal ranges). JAK2 mutation is detected (VAF = 10.1%) on peripheral blood granulocytes. A BM biopsy (a–c) features striking hypocellularity without morphologic atypia. A slight decrease in the myeloid-to-erythroid ratio is noted with mildly increased, polymorphic megakaryocytes consisting of mature-looking to giant, hyperlobulated forms. There is no evidence of BM fibrosis and CD34+ blasts are not increased. The clinicopathologic synopsis supports MPN, but the very unusual morphologic picture favors a provisional diagnosis of MPN-U. Hypocellularity is uncommon in clonal myeloid disorders in general and barely reported in both early and chronic phase MPN. It may nonetheless be encountered in late-stage disease with the classical picture of MF with myeloid metaplasia. In this setting, the BM niche is overwhelmed by the stromal component with consequent peripheralization of hematopoietic cells. In the current case, the diagnosis of MPN is strongly supported by the laboratory findings, by the presence of a driver mutation, and by megakaryocyte morphology. Even though most clues point towards ET, the relative increase in the erythroid progenitors and Hb levels at the upper limit of normal cannot definitively rule out early phase PV with ET-like presentation and very atypical BM morphology.
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.