Essential thrombocythemia and its mimickers in the pediatric age: clinical, histopathological and genetic features

Thrombocytosis of the pediatric age can be due to a variety of causes, including: (i) myeloproliferative neoplasms (MPNs); (ii) chronic infectious and/or inflammatory disorders (i.e. secondary thrombocytosis [ST]); and (iii) hereditary or familial thrombocytosis (FT). Essential Thrombocythemia (ET) is the commonest MPN of the pediatric age and its differential diagnosis from ST/FT can be challenging. A thorough characterization of the clinical, histological and genetic features of pediatric ET (PedET) may support the diagnostic workup of this disorder, favoring its clinical management. This study aims: (i) to describe the clinical-pathological features of PedET; (ii) to explore the genetic landscape of PedET; (iii) to assess histological and/or genetic clues supporting the differential diagnosis between PedET and ST. This multicentric study considered a retrospective series of 39 pediatric MPNs with thrombocytosis, for which adequate BM samples were available for histological review. Clinical and laboratory data were collected from the files of each participating unit. The original BM samples were reviewed by 2 hematopathologists, who also assessed the following histological parameters: (i) BM cellularity; (ii) myeloid to erythroid ratio; (iii) myeloid and erythroid maturation; (iv) megakaryocytic number, clustering and cytological features; (v) presence/absence of intravascular hematopoiesis; (vi) presence/absence of adipocyte cords along bone trabeculae; (vii) grade of BM fibrosis; (viii) percentage of BM myeloid precursor. Genetic data for driver and non-driver gene mutations were collected in all available cases. The results on PedET were confronted with a series of 16 ST/FT cases to identify histological features supporting the differential diagnosis between these entities. Statistical analysis was performed by non-parametric tests for quantitative (Wilcoxon-Mann-Whitney test) and qualitative variables (Fisher’s exact test). A histological score was produced by logistic regression and ROC analysis. Differences between subgroups were considered statistically significant for p-values <0.05. The MPN population included 18 males and 21 females with median age at diagnosis of 12 years. Histological assessment of the BM led to a diagnosis of PedET in 35/39 (89.7%), pediatric Primary Myelofibrosis (PedPMF) in 3/39 (7.7%) and MPN unclassifiable in 1/39 (2.6%) cases. Complete clinical and laboratory data were available in 33/35 (94.3%) PedET cases. Microvascular symptoms were reported in 19/33 (57.6%), acquired von Willebrand disease in 11/16 (68.8%), thrombotic events at diagnosis in 3/33 (9.1%) and bleeding symptoms at diagnosis in 5/33 (15.2%) cases. All of these were more frequently documented in PedET than in ST/FT. Molecular analysis disclosed JAK2 mutations in 12/35 (34.3%), CALR mutations in 5/35 (14.3%), and MPL mutations in 1/35 (2.9%) PedET cases. Non-driver gene mutations were absent in all tested samples. Histological assessment of PedET disclosed higher numbers of megakaryocytes with hypersegmented nuclei, more frequent megakaryocytic clusters and more extensive intravascular hematopoiesis in PedET than in ST/FT. An integrated score considering these histological parameters was associated with high diagnostic yield. PedET is a rare hematopoietic neoplasm that can be closely mimicked by other MPN (PedPMF) and by ST/FT. Molecular studies have high specificity but limited sensitivity in the differential diagnosis between PedET and ST/FT. Histological evaluation of the BM greatly supports the diagnostic workup and an integrated score considering megakaryocytic features and intravascular hematopoiesis is associated with high diagnostic yield. Further studies on larger cohorts of patients are needed to confirm these preliminary findings and to better elucidate the clinical-biological features of PedET.