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.
A 17-year-old Caucasian male, a high school student from Missouri was referred for evaluation of unexplained erythrocytosis. He reported a myriad of symptoms including nausea, vomiting, abdominal pain, weight loss, fatigue, headaches, cold hands and feet with numbness and tingling, hyperhidrosis, palpitations, and pruritus. He was a non-smoker without illicit drug or hormone use. Family history was unremarkable. On physical examination, no cutaneous, abdominal or neurological abnormalities were noted. A review of serial blood counts showed a consistent elevation in Hgb >16.5 g/dl, with peak Hgb/Hct of 18.3 g/dl/52.4% and normal leukocyte and platelet counts. PV was excluded with a negative JAK2V617F/exon 12 mutation screen and elevated EPO at 22.6 mIU/mL (normal range; 2.6–18.5 mIU/mL). Bone marrow aspirate/biopsy was without features of a MPN. Hereditary erythrocytosis evaluation did not reveal high-affinity Hgb variants or mutations in 2,3-Bisphosphoglycerate Mutase (BPGM)(exons 1–4), EPOR (exon 8), or oxygen-sensing pathway proteins, including hypoxia-inducible factor 2 α (HIF2A) encoded by endothelial PASS domain protein 1 (EPAS1) (exons 9 and 12), prolyl hydroxylase 2 (PHD2) encoded by egl-9 family hypoxia-inducible factor 1(EGLN1)(exons 1-5), von Hippel Lindau (VHL) (three coding exons and intron/exon boundaries). Chest/abdominal imaging, arterial blood gas, transthoracic echocardiogram with shunt study, urinary catecholamines/metanephrines were unremarkable. Interestingly, MRI brain/spine revealed multiple cerebrovascular malformations; both developmental venous anomalies and cavernous hemangiomas in the frontal and temporal regions. Accordingly, the cerebrovascular malformations were hypothesized to be a plausible link to the patient’s erythrocytosis. Surgical intervention was not feasible due to the presence of multiple anomalies. He was initiated on phlebotomies with marked improvement in symptoms; thereafter, need for periodic phlebotomies was determined by symptoms rather than a target Hct value. This previously published case underscores the importance of a systematic diagnostic approach to JAK2 unmutated erythrocytosis [].