Overview of histiocytic and dendritic disorders by the 5th version of WHO Classifi cation of Hematolymphoid Tumours from 2022.

BACKGROUND: Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. PURPOSE: This text provides an overview of histiocytoses as described in the WHO Classification 2022.

Blastic Plasmacytoid Dendritic Cell Neoplasm, from a Dermatological Point of View.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological malignancy derived from the precursors of plasmacytoid dendritic cells. Although disease awareness has increased over time, BPDCN represents a rare disease with an aggressive clinical course and a dismal prognosis. Due to the overlap in clinical and histological features with a large spectrum of inflammatory and neoplastic diseases, BPDCN is difficult to diagnose. Furthermore, given the rarity of the disease, treatment options for BPDCN are limited, sometimes changing by practitioner and hospitals. Treatment options range from conventional chemotherapy to the recently approved biologic agent tagraxofusp and stem cell transplantation. Therefore, a multidisciplinary approach with coordination among dermatologists, pathologists, and hematologists is ultimately imperative to reach the correct diagnosis and management of BPDCN.

Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis.

Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.

Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell (cDC1) activation and tumor infiltration.

Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) inhibits tumor growth and boosts immune responses against cancer. However, whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely understood. Here, we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into tumor. Pharmacological inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8+ T cell responses. Mechanistically, targeting BCL9/BCL9L promoted antigen presentation in tumors. This is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 axis. Importantly, using single-cell transcriptomics analysis, we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type (WT) cDC1 at activation and antigen presentation via NF-κB/IRF1 signaling. Together, we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens, as well as CD8+ T cell activation and tumor infiltration. Targeting BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

Genome-wide DNA methylation-analysis of blastic plasmacytoid dendritic cell neoplasm identifies distinct molecular features.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid dendritic cells (pDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BPDCN patients supplemented by WES and RNA-seq as well as ATAC-seq on selected cases. We determined the BPDCN DNA methylation profile and observed a dramatic loss of DNA methylation during malignant transformation from early and mature DCs towards BPDCN. DNA methylation profiles further differentiate between BPDCN, AML, CMML, and T-ALL exhibiting the most striking global demethylation, mitotic stress, and merely localized DNA hypermethylation in BPDCN resulting in pronounced inactivation of tumor suppressor genes by comparison. DNA methylation-based analysis of the tumor microenvironment by MethylCIBERSORT yielded two, prognostically relevant clusters (IC1 and IC2) with specific cellular composition and mutational spectra. Further, the transcriptional subgroups of BPDCN (C1 and C2) differ by DNA methylation signatures in interleukin/inflammatory signaling genes but also by higher transcription factor activity of JAK-STAT and NFkB signaling in C2 in contrast to an EZH2 dependence in C1-BPDCN. Our integrative characterization of BPDCN offers novel molecular insights and potential diagnostic applications.

Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.

[Blastic plasmacytoid dendritic cell tumor treated with DVT regimen: a case report and literature review].

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy, there is no standard treatment and the prognosis is very poor. Affiliated Zhongshan Hospital of Dalian University report a case of 85-year-old BPDCN male patient treated with DVT regimen (decitabine combined with Venetoclax and thalidomide) and achieved complete remission. The patient with skin nodules and the pathology diagnosed BPDCN, the next generation sequencing of skin nodules showed mutations of IDH2 and ASXL1. DVT (decitabine combined with Venetoclax and thalidomide) has significant efficacy with rapid and deep remission for BPDCN, and the adverse effects is less, especially suitable for elderly patients who cannot tolerate intense chemotherapy.

Diagnóstico clínico-patológico de la neoplasia de células dendríticas plasmocitoides blásticas: reporte de 3 casos / Clinicopathological diagnosis of blastic plasmacytoid dendritic cell neoplasm: Report of three cases

La neoplasia de células dendríticas plasmocitoides blásticas (NCDPB) es una enfermedad de baja incidencia y muy mal pronóstico, que con gran frecuencia afecta a la piel, pudiendo ser el primer signo clínico de la enfermedad. Se presentan 3 casos en los que la primera manifestación de la enfermedad fueron lesiones cutáneas. Se describe el cuadro clínico, los hallazgos histopatológicos e inmunohistoquímicos, así como los estudios de extensión y las características moleculares de las 3 neoplasias. Uno de los pacientes permanece en un ensayo clínico con IMGN632, una molécula dirigida contra CD123, mientras que los otros 2 pacientes fallecieron tras distintos regímenes terapéuticos. La NCDPB es una entidad de diagnóstico complejo. Esto, unido a su mal pronóstico, obligan a una comunicación clínico-patológica estrecha que acelere su diagnóstico y ofrezca alternativas terapéuticas precoces con fármacos dirigidos contra dianas moleculares específicas de esta entidad. (AU)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease with a poor prognosis. It frequently affects the skin; indeed, dermal lesions may be the first clinical manifestation. We report three cases of BPDCN where the patients presented with skin lesions and describe the clinical, histopathological and immunohistochemical findings, its molecular characteristics and metastatic work-up. One of the patients remains in a clinical trial with IMGN632, a molecule directed against CD123, while the other two patients died after different therapeutic regimens. BPDCN is a complex diagnostic challenge which, together with its poor prognosis, requires close clinical-pathological cooperation in order to accelerate its diagnosis and offer early therapeutic alternatives with drugs directed against specific molecular targets. (AU)

Diagnóstico clínico-patológico de la neoplasia de células dendríticas plasmocitoides blásticas: reporte de 3 casos / Clinicopathological diagnosis of blastic plasmacytoid dendritic cell neoplasm: Report of three cases

La neoplasia de células dendríticas plasmocitoides blásticas (NCDPB) es una enfermedad de baja incidencia y muy mal pronóstico, que con gran frecuencia afecta a la piel, pudiendo ser el primer signo clínico de la enfermedad. Se presentan 3 casos en los que la primera manifestación de la enfermedad fueron lesiones cutáneas. Se describe el cuadro clínico, los hallazgos histopatológicos e inmunohistoquímicos, así como los estudios de extensión y las características moleculares de las 3 neoplasias. Uno de los pacientes permanece en un ensayo clínico con IMGN632, una molécula dirigida contra CD123, mientras que los otros 2 pacientes fallecieron tras distintos regímenes terapéuticos. La NCDPB es una entidad de diagnóstico complejo. Esto, unido a su mal pronóstico, obligan a una comunicación clínico-patológica estrecha que acelere su diagnóstico y ofrezca alternativas terapéuticas precoces con fármacos dirigidos contra dianas moleculares específicas de esta entidad. (AU)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease with a poor prognosis. It frequently affects the skin; indeed, dermal lesions may be the first clinical manifestation. We report three cases of BPDCN where the patients presented with skin lesions and describe the clinical, histopathological and immunohistochemical findings, its molecular characteristics and metastatic work-up. One of the patients remains in a clinical trial with IMGN632, a molecule directed against CD123, while the other two patients died after different therapeutic regimens. BPDCN is a complex diagnostic challenge which, together with its poor prognosis, requires close clinical-pathological cooperation in order to accelerate its diagnosis and offer early therapeutic alternatives with drugs directed against specific molecular targets. (AU)

Leukemic mutation FLT3-ITD is retained in dendritic cells and disrupts their homeostasis leading to expanded Th17 frequency.

Dendritic cells (DC) are mediators between innate and adaptive immune responses to pathogens and tumors. DC development is determined by signaling through the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3) in bone marrow myeloid progenitors. Recently the naming conventions for DC phenotypes have been updated to distinguish between "Conventional" DCs (cDCs) and plasmacytoid DCs (pDCs). Activating mutations of FLT3, including Internal Tandem Duplication (FLT3-ITD), are associated with poor prognosis for acute myeloid leukemia (AML) patients. Having a shared myeloid lineage it can be difficult to distinguish bone fide DCs from AML tumor cells. To date, there is little information on the effects of FLT3-ITD in DC biology. To further elucidate this relationship we utilized CITE-seq technology in combination with flow cytometry and multiplex immunoassays to measure changes to DCs in human and mouse tissues. We examined the cDC phenotype and frequency in bone marrow aspirates from patients with AML to understand the changes to cDCs associated with FLT3-ITD. When compared to healthy donor (HD) we found that a subset of FLT3-ITD+ AML patient samples have overrepresented populations of cDCs and disrupted phenotypes. Using a mouse model of FLT3-ITD+ AML, we found that cDCs were increased in percentage and number compared to control wild-type (WT) mice. Single cell RNA-seq identified FLT3-ITD+ cDCs as skewed towards a cDC2 T-bet- phenotype, previously shown to promote Th17 T cells. We assessed the phenotypes of CD4+ T cells in the AML mice and found significant enrichment of both Treg and Th17 CD4+ T cells in the bone marrow and spleen compartments. Ex vivo stimulation of CD4+ T cells also showed increased Th17 phenotype in AML mice. Moreover, co-culture of AML mouse-derived DCs and naïve OT-II cells preferentially skewed T cells into a Th17 phenotype. Together, our data suggests that FLT3-ITD+ leukemia-associated cDCs polarize CD4+ T cells into Th17 subsets, a population that has been shown to be negatively associated with survival in solid tumor contexts. This illustrates the complex tumor microenvironment of AML and highlights the need for further investigation into the effects of FLT3-ITD mutations on DC phenotypes and their downstream effects on Th polarization.

SHIV-C109p5 NHP induces rapid disease progression in elderly macaques with extensive GI viral replication.

CCR5-tropic simian/human immunodeficiency viruses (SHIV) with clade C transmitted/founder envelopes represent a critical tool for the investigation of HIV experimental vaccines and microbicides in nonhuman primates, although many such isolates lead to spontaneous viral control post infection. Here, we generated a high-titer stock of pathogenic SHIV-C109p5 by serial passage in two rhesus macaques (RM) and tested its virulence in aged monkeys. The co-receptor usage was confirmed before infecting five geriatric rhesus macaques (four female and one male). Plasma viral loads were monitored by reverse transcriptase-quantitative PCR (RT-qPCR), cytokines by multiplex analysis, and biomarkers of gastrointestinal damage by enzyme-linked immunosorbent assay. Antibodies and cell-mediated responses were also measured. Viral dissemination into tissues was determined by RNAscope. Intravenous SHIV-C109p5 infection of aged RMs leads to high plasma viremia and rapid disease progression; rapid decrease in CD4+ T cells, CD4+CD8+ T cells, and plasmacytoid dendritic cells; and wasting necessitating euthanasia between 3 and 12 weeks post infection. Virus-specific cellular immune responses were detected only in the two monkeys that survived 4 weeks post infection. These were Gag-specific TNFα+CD8+, MIP1ß+CD4+, Env-specific IFN-γ+CD4+, and CD107a+ T cell responses. Four out of five monkeys had elevated intestinal fatty acid binding protein levels at the viral peak, while regenerating islet-derived protein 3α showed marked increases at later time points in the three animals surviving the longest, suggesting gut antimicrobial peptide production in response to microbial translocation post infection. Plasma levels of monocyte chemoattractant protein-1, interleukin-15, and interleukin-12/23 were also elevated. Viral replication in gut and secondary lymphoid tissues was extensive.IMPORTANCESimian/human immunodeficiency viruses (SHIV) are important reagents to study prevention of virus acquisition in nonhuman primate models of HIV infection, especially those representing transmitted/founder (T/F) viruses. However, many R5-tropic SHIV have limited fitness in vivo leading to many monkeys spontaneously controlling the virus post acute infection. Here, we report the generation of a pathogenic SHIV clade C T/F stock by in vivo passage leading to sustained viral load set points, a necessity to study pathogenicity. Unexpectedly, administration of this SHIV to elderly rhesus macaques led to extensive viral replication and fast disease progression, despite maintenance of a strict R5 tropism. Such age-dependent rapid disease progression had previously been reported for simian immunodeficiency virus but not for R5-tropic SHIV infections.

Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial.

Autologous natural dendritic cells (nDCs) treatment can induce tumor-specific immune responses and clinical responses in cancer patients. In this phase III clinical trial (NCT02993315), 148 patients with resected stage IIIB/C melanoma were randomized to adjuvant treatment with nDCs (n = 99) or placebo (n = 49). Active treatment consisted of intranodally injected autologous CD1c+ conventional and plasmacytoid DCs loaded with tumor antigens. The primary endpoint was the 2-year recurrence-free survival (RFS) rate, whereas the secondary endpoints included median RFS, 2-year and median overall survival, adverse event profile, and immunological response The 2-year RFS rate was 36.8% in the nDC treatment group and 46.9% in the control group (p = 0.31). Median RFS was 12.7 months vs 19.9 months, respectively (hazard ratio 1.25; 90% CI: 0.88-1.79; p = 0.29). Median overall survival was not reached in both treatment groups (hazard ratio 1.32; 90% CI: 0.73-2.38; p = 0.44). Grade 3-4 study-related adverse events occurred in 5% and 6% of patients. Functional antigen-specific T cell responses could be detected in 67.1% of patients tested in the nDC treatment group vs 3.8% of patients tested in the control group (p < 0.001). In conclusion, while adjuvant nDC treatment in stage IIIB/C melanoma patients generated specific immune responses and was well tolerated, no benefit in RFS was observed.

Blastic Plasmacytoid Dendritic Cell Neoplasm: A Comprehensive Review of the Disease, Central Nervous System Presentations, and Treatment Strategies.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with poor outcomes. The World Health Organization (WHO) redefined BDCN as a distinct disease entity in 2016. BPDCN arises from plasmacytoid dendritic cells, manifesting primarily in the skin, bone marrow, and lymph nodes, occasionally involving the central nervous system (CNS). This presents challenges in diagnosis and treatment, with CNS involvement often overlooked in standard diagnostic workups due to BPDCN's rarity and patients often being neurologically asymptomatic at diagnosis. CNS involvement typically emerges during relapse, yet clinical trials often exclude such cases, limiting our understanding of its development and treatment. Treatment options for CNS involvement include intrathecal (IT) chemotherapies like methotrexate and cytarabine, often in combination with systemic agents. Tagraxofusp and traditional regimens for acute myeloid leukemia show limited success at preventing CNS relapse, prompting exploration of combined therapies like hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) with venetoclax and adding IT chemotherapy to other backbones. Ongoing clinical trials investigating emerging therapies offer hope despite limited focus on CNS implications. Trials incorporating CNS-involved patients aim to pioneer novel treatment approaches, potentially reshaping BPDCN management. Understanding CNS involvement's complexities in BPDCN remains crucial for tailored treatments and better patient outcomes.

Diagnostic management of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in close interaction with therapeutic considerations.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001-2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

A blastic plasmacytoid dendritic cell neoplasm-like immunophenotype is negatively associated with CEBPA bZIP mutation and predicts unfavorable prognosis in acute myeloid leukemia.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.