A 46-year-old woman presents with a long-lasting history of thrombocytosis (mean platelets: 500 × 109/L) and a putative clinical diagnosis of ET treated with low-dose aspirin. A BM biopsy () is performed 20 years after clinical onset and shows hypercellular, trilinear hematopoiesis with normal myeloid-to-erythroid ratio, mildly left shifted granulopoiesis, and increased, mature-looking megakaryocytes. Blasts account for 3–4% of the hematopoietic cells and reticulin fibrosis is not increased. Driver mutations of JAK2, CALR and MPL are not detected, but targeted NGS documents the L56S RUNX1 variant. The overall morphological and molecular findings exclude ET and suggest an alternative diagnosis of RUNX1-mutated myeloid neoplasm with thrombocytosis.\nGermline RUNX1 mutations are reported in inherited forms of platelet disorders with a predisposition to myeloid malignancies []. Acquired RUNX1 derangements are instead relatively common in MDS, MDS/MPN, AML, and in contexts akin to CHIP []. In the present case, the unremarkable family history, the clinical presentation, and the histological findings exclude such diagnoses and favors MPN-U. Of note, rare cases of MPN feature RUNX1 mutations and typically undergo myelofibrotic and/or blastic progression [,]. This and 3 similar cases published by Cattaneo and colleagues [] disclose the unique features of an MPN with “high risk” genetics and an indolent, ET-like clinical course.
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.