Disease presentation and immunophenotype characteristics in 257 patients with blastic plasmacytoid dendritic cell neoplasm: A pethema/PALG study

Abstract

Abstract Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy characterized by a complex clinical presentation. Comprehensive characterization at diagnosis is essential for proper classification and therapeutic decisions. Immunophenotype and/or immunohistochemistry are currently mandatory diagnostic criteria for confirming this neoplasm. However, large series describing marker features at diagnosis are scarce. Material This multinational retrospective study performed by PALG and PETHEMA groups registered BPDCN patients from July 1999 to 2025 (EPI-BLAS project). Local data for clinical presentation, morphology, immunophenotype, and immunohistochemistry was collected from participating centers and reviewed centrally. BPDCN classification was made locally based on WHO criteria applicable at the time of diagnosis. Results A total of 257 patients diagnosed with BPDCN were included in the multinational PETHEMA and PALG registry. Most were male (78%), median age was 66 years old (range, 15-92), bone marrow involvement (>5% blasts) was documented in 75% (177/237, 20 data not available [NA]), and peripheral blood in 62% (103/165, 92 NA). Regarding extramedullary involvement, 197 (81%) out of 242 with available data had skin involvement, and 49% (131/237, 20 NA) had lymphadenopathy. A lumbar puncture was performed at diagnosis in 77% (168/217, 40 NA) patients and CNS infiltration was documented in 48 (29%) of them. Disease was restricted to the skin in (10%) 25 patients. Immunophenotypic and/or immunohistochemical information was available in 236 patients. Immunohistochemistry (IHQ) studies were conducted on 178 patients (115 skin biopsies, 47 bone marrow biopsies, 13 lymph nodes, 1 salivary gland, and 1 spleen specimen). Flow cytometry (FC) analyses were performed in 244 patients (179 bone marrow aspirates, 26 peripheral blood samples, 16 skin biopsies, 21 cerebrospinal fluid (CSF) samples, and 2 lymph nodes). In 6 additional patients, the specific technique used could not be determined due to insufficient documentation. Skin biopsies from IHQ showed in most cases positive expression of CD4 (94/96, 98%, 19 NA), CD56 (92/99, 93%, 16 NA), CD123 (66/66, 100%, 49 NA), CD304 (1/1, 100%, 114 NA), and TCL1 (6/7, 86%, 108 NA). CD303 and TCF4 expression were never assessed. Negative expression for CD3, CD14, CD19, CD34, lysozyme and myeloperoxidase (MPO) were found in 94% (79/84, 31 NA), 100% (6/6, 109 NA), 100% (2/2, 113 NA), 98% (55/56, 46 NA), 92% (11/12, 77 NA) and 98% (55/56, 45 NA), respectively. When performed, FC analysis of bone marrow detected BPDCN cells in 95% of cases (170/179), and the vast majority showed positivity for CD4 (132/141, 94%, 29 NA), CD56 (117/147, 80%, 23 NA), CD123 (143/147, 97%, 23 NA), CD304 (12/14, 86%, 156 NA), and TCL1 (22/22, 100%, 148 NA). CD303 was positive in 29% (2/7, 163 NA). TCF4 expression was never assessed. CD3, CD14, CD19, CD34, lysozyme, and MPO were consistently negative in 98% (89/91, 79 NA), 98% (96/98, 52 NA), 95% (112/118, 52 NA), 74% (100/135, 35 NA), 75% (3/4, 166 NA), and 93% (102/110, 60 NA), respectively. In 20% (30/149, 21 NA) of patients, more than one leukemic population was identified by FC in bone marrow, potentially representing different stages of plasmacytoid dendritic cells (pDC) differentiation. Among 23 BPDCN patients with ≤5% morphological blast cells in bone marrow and with available FC analyses, 18 patients (78%) showed BPDCN cells (median 1.95% blasts, range 0.01% to 20%), 2 (10%) showed pDC with normal immunophenotypic profile; and 5 (22%) showed no evidence of pDCs or BPDCN. Conclusion Our large registry study in this rare disease showed skin and bone marrow involvement in the vast majority of patients. Half of BPCN patients had lymph node involvement, and 29% CNS disease. IHQ and FC analyses showed positivity for CD123, CD4 and CD56 in almost all samples. CD304 and TCL1 were also positive in almost all cases, but these surface antigen markers were only tested in a minority of samples. FC analyses could detect BPDCN cells in most cases without bone marrow morphological infiltration, highlighting the role of FC assessment in this tissue. The consistent implementation of well-defined markers, particularly those outlined in the WHO 2022 classification, could further strengthen diagnostic precision of BPDCN. Disclosures The EPI-BLAS registry was partially funded by Menarini.