Frequent <i>NPM1</i> mutation, monoblastic/monocytic origin and prognostic significance of organ and system involvement in myeloid sarcoma: a multicenter study

Myeloid sarcoma (MS) is a tumorous extramedullary proliferation of blast or blast equivalent cells (e.g., promonocytes or promyelocytes). The most frequent cutaneous presentation is often referred to as leukemia cutis (LC). These lesions, especially without the clinical context of a known bone marrow disease, pose a differential diagnostic challenge. In this retrospective multicenter clinico-pathological study on 154 patients with MS or LC, 169 samples were analyzed by morphology, immunohistochemistry, and fluorescent in situ hybridization, and a subset by additional sequencing [TP53]. The majority of cases were lysozyme positive (diffuse in 91% and focal in 5%), 51% showed diffuse and 6% focal expression of CD56, and IRF8 was strongly positive in 31% of the lesions. Lack of myeloperoxidase (MPO), CD117, and CD34 expression was observed in 27%, 39%, and 58%, respectively. PU.1 was positive in almost all instances (95%), but BRAF V600E was consistently negative. CD123 was diffusely (13%) or focally (25%) positive, which, in addition to frequent CD4 (73%) and CD56 expression, pointed to a phenotypic overlap with blastic plasmacytoid dendritic cell neoplasms. Survival analysis revealed that MS occurring at sanctuary sites (CNS, orbit, ovary, and testis) was characterized by excellent survival. Similarly to histiocytoses, there was a prognostic difference between isolated and multisystemic involvement by MS. Patients who underwent allogeneic hematopoietic stem cell transplantation showed significantly improved survival. In conclusion, this multicenter study suggests that most MS are of myelomonocytic/monoblastic origin, a high proportion of them are NPM1 mutated, and may lack expression of MPO and CD34. NPM1 mutation-specific antibodies should be integrated into the diagnostic panels for MS or LC, while IRF8 and PU.1 are not recommended as they cannot distinguish MS from histiocytic neoplasms.