Pathomorphological diagnosis of Ph-negative chronic myeloproliferative neoplasms in children

BCR::ABL/Ph-negative chronic myeloproliferative neoplasms (CMPN) in children differ from those in adults in clinical manifestations and genetic alterations. Taking into account the well-known physiology of hematopoiesis in children, it seems important to compare the histological features of CMPN in pediatric patients with the criteria for the diagnosis of these diseases in adults specified in the World Health Organization (WHO) classification. In pediatric practice, the interpretation of changes in hematopoiesis in patients with CMPN without any established driver mutation has a particular importance for differential diagnosis with secondary thrombocytosis and erythrocytosis. For our analysis, we used bone marrow trephine biopsy specimens from the biobank of the Pathology Department of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. They had been obtained between 2016 and 2023 from 70 patients for initial histological examination. The final clinical diagnosis for these patients was CMPN. The frequency of the most common histological changes in hematopoiesis was assessed retrospectively. We compared our results with the data from the WHO classification, analysed the differences in morphological changes in the subgroups of patients with essential thrombocythemia with an established mutation or without it, assessed the relationship between the morphological changes and clinical symptoms of CMPN. The changes in hematopoiesis in children with CMPN are predominantly similar to those in adults, however there are differences in the morphology of megakaryocytes (scarcity of giant cells with hypersegmented nuclei (staghorn-like), an increased number of small and naked nuclei cells). In addition, bone marrow cellularity assessment has a low diagnostic value in differentiating between essential thrombocythemia and polycythemia vera in children. There are no differences in morphology in the subgroups of patients with essential thrombocythemia with an established mutation or without it. No statistically significant association between clinical symptoms of the disease and any of the morphological features of CMPN was found. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation.

1. van der Walt J., Orazi A., Arber D.A. Diagnostic bone marrow haematopathology. Cambridge University Press; 2020. DOI: 10.1017/9781316535042

2. WHO classification of tumours editorial board. Haematolymphoid tumors. Lyon (France): International agency for research on cancer; 2022 (WHO classification of tumours series, 5th ed.; vol. 11). [Electronic resource] URL: https://tumourclassification.iarc.who.int/chapters/63 (accessed 25.04.2024).

3. Hasle H. Incidence of essential thrombocythaemia in children. Br J Haematol 2000; 110: 751. DOI: 10.1046/j.1365-2141.2000.02239-7.x

4. El-Sharkawy F., Margolskee E. Pediatric Myeloproliferative Neoplasms. Clin Lab Med 2021; 41: 529–40. DOI: 10.1016/j.cll.2021.04.010

5. Thiele J., Kvasnicka H.M., Facchetti F., Franco V., van der Walt J., Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 2005; 90: 1128–32.

6. Karow A., Nienhold R., Lundberg P., Peroni E., Putti M.C., Randi M.L., Skoda R.C. Mutational profile of childhood myeloproliferative neoplasms. Leukemia 2015; 29: 2407–9. DOI: 10.1038/leu.2015.205

7. Randi M.L., Putti M.C., Scapin M., Pacquola E., Tucci F., Micalizzi C., et al. Pediatric patients with essential thrombocythemia are mostly polyclonal and V617FJAK2 negative. Blood 2006; 108: 3600–2. DOI: 10.1182/blood-2006-04-014746

8. Farruggia P., D’Angelo P., La Rosa M., et al. MPL W515L mutation in pediatric essential thrombocythemia. Pediatr Blood Cancer 2013; 60: E52–4. DOI: 10.1002/pbc.24500

9. Proytcheva M. Bone marrow evaluation for pediatric patients. Int J Lab Hematol 2013; 35: 283–9. DOI: 10.1111/ijlh.12073

10. Leguit R.J., Orazi A., Kucine N., Kvasnicka H.M., Gianelli U., Arber D.A., et al. EAHP 2020 workshop proceedings, pediatric myeloid neoplasms. Virchows Arch 2022; 481: 621–46. DOI: 10.1007/s00428-022-03375-8

11. Putti M.C., Pizzi M., Bertozzi I., Sabattini E., Micalizzi C., Farruggia P., et al. Bone marrow histology for the diagnosis of essential thrombocythemia in children: a multicenter Italian study. Blood 2017; 129: 3040–2. DOI: 10.1182/blood-2017-01-761767

12. Randi M.L., Geranio G., Bertozzi I., Micalizzi C., Ramenghi U., Tucci F., et al. Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort. Br J Haematol 2015; 169: 584–9. DOI: 10.1111/bjh.13329

13. Longo D.L. Bone marrow in aging: changes? Yes; clinical malfunction? Not so clear. Blood 2008; 112: sci-1–sci-1. DOI: 10.1182/blood.V112.11.sci-1.sci-1

14. Friebert S.E., Shepardson L.B., Shurin S.B., Rosenthal G.E., Rosenthal N.S. Pediatric bone marrow cellularity: are we expecting too much? J Pediatr Hematol Oncol 1998; 20: 439–43. DOI: 10.1097/00043426-199809000-00006

15. Wong J., Jackson R., Chen L., Song J., Pillai R., Afkhami M., et al. Determination of age-dependent bone marrow normocellularity. Am J Clin Pathol 2024; 161: 170–6. DOI: 10.1093/ajcp/aqad129

16. Ng Z.Y., Fuller K.A., Mazza-Parton A., Erber W.N. Morphology of myeloproliferative neoplasms. Int J Lab Hematol 2023; 45 Suppl 2: 59–70. DOI: 10.1111/ijlh.14086