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Diagnosis and Discussion: Case 1140

Diagnosis and Discussion

The patient was diagnosed with acute myeloid leukemia (AML). The immunophenotype of the blasts raised the possibility of  acute promyelocytic leukemia (APML) due to the CD34 and HLA-DR negativity. A PML-RARA FISH analysis was performed on the peripheral blood, and it was negative. A positive NPM1 immunohistochemical (IHC) stain performed on the core biopsy suggested a potential NPM1 mutation. Next generation sequencing revealed mutations in NPM1, FLT3, IDH2, NRAS, and SRSF2, confirming the diagnosis of NPM1-mutated AML.

NPM1-mutated AML, also known as AML with cytoplasmic nucleophosmin, is a unique entity recognized by the World Health Organization (WHO 5th edition) and the 2022 International Consensus Classification [1,2,3]. It represents the largest molecular subtype of AML, accounting for about one-third of adult cases [3]. NPM1 mutant specific IHC stains are helpful in identifying potential NPM1 mutations [1,3]. The persistence of an NPM1 mutation after remission indicates active disease, thus IHC and other methods of identification can be useful in follow-up settings [3]. Frequently, NPM1 mutations are detected by PCR and next-generation sequencing [3]. The mutation is most often a 4 bp insertion in exon 12 of the NPM1 gene [1,7].

The histopathological findings of NPM1 mutated AML may include a hypercellular marrow, myelomonocytic or monocytic differentiation, multilineage dysplasia, and blasts with cup-like morphology [1]. The immunophenotype identified on flow cytometry frequently lacks CD34 expression and demonstrates expression of CD33, CD117, CD123, CD13 and HLA-DR [4,5].  An APML-like immunophenotype may also been seen, in which the blasts are CD34 negative, HLA-DR negative, CD117 positive, and myeloperoxidase positive [6]. The essential diagnostic criteria identified by the WHO 5th Edition includes a myeloid neoplasm with increased peripheral blood and/or bone marrow blasts (which may be <20%), detection of NPM1 mutation, and no history of cytotoxic therapy [1]. According to the ICC guidelines, the required blast count for NPM1-mutated AML is >10% blasts [2].

References

  1. Khoury JD, Loghavi S, Gujral S, et al. Acute myeloid leukaemia with NPM1 mutation. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2024 [cited 2024 December 10]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from https://tumourclassification.iarc.who.int/chapters/63.
  2. Weinberg OK, Porwit A, Orazi A, et al. The International Consensus Classification of acute myeloid leukemia. Virchows Archiv. Published online October 20, 2022. doi:https://doi.org/10.1007/s00428-022-03430-4
  3. Falini B, Dillon R. Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML. Blood cancer discovery. 2024;5(1):8-20. doi:https://doi.org/10.1158/2643-3230.bcd-23-0144
  4. Nomdedeu J, Bussaglia E, Villamor N, et al. Immunophenotype of acute myeloid leukemia with NPM mutations: Prognostic impact of the leukemic compartment size. Leukemia Research. 2011;35(2):163-168. doi:https://doi.org/10.1016/j.leukres.2010.05.015
  5. Liu YR, Zhu HH, Ruan GR, et al. NPM1-mutated acute myeloid leukemia of monocytic or myeloid origin exhibit distinct immunophenotypes. Leukemia Research. 2013;37(7):737-741. doi:https://doi.org/10.1016/j.leukres.2013.03.009
  6. Mason EF, Kuo FC, Hasserjian RP, Seegmiller AC, Pozdnyakova O. A distinct immunophenotype identifies a subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. American Journal of Hematology. 2017;93(4):504-510. doi:https://doi.org/10.1002/ajh.25018
  7. Martelli MP, Rossi R, Venanzi A, et al. Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML. Blood. Published online August 3, 2021. doi:https://doi.org/10.1182/blood.2021012732