Cases Of Blastic Plasmacytoid Dendritic Cell Neoplasm Research Articles

TET2 mutations, myelodysplastic features, and a distinct immunoprofile characterize blastic plasmacytoid dendritic cell neoplasm in the bone marrow.

Distinguishing blastic plasmacytoid dendritic cell neoplasm (BPDCN) from acute myeloid leukemia (AML) is gaining increased importance because of emerging differences in therapeutic approaches, and this distinction can be problematic in bone marrow specimens. We identified retrospectively 16 patients with bone marrow involvement by BPDCN: 11 men and 5 women with a median age of 62.5 years (range, 19-86 years). Myelodysplastic changes were observed in five patients. Immunophenotypic analysis showed that the neoplastic cells were positive for CD4, CD123, TCL-1, and HLA-DR and were negative for CD3, CD8, CD13, CD19, CD34, and myeloperoxidase. Other antigens expressed by subsets of BPDCN cases included the following: CD56 (13/15; 81%), CD33 (7/10; 70%), CD7 (11/14; 69%), TdT (5/15; 33%), CD2 (5/11; 31%), CD117 (2/9; 22%), and CD5 (2/13; 15%). Conventional cytogenetic analysis showed chromosomal abnormalities in 6 of 13 (46%) cases analyzed, of which 3 cases had -13/13q-. Targeted next-generation sequencing performed on five BPDCN cases identified TET2 (ten eleven translocation 2) mutations and no other AML-associated mutations. In conclusion, BPDCN in the bone marrow has a characteristic immunoprofile (CD4+, CD56+, CD123+, and TCL-1+) and appears to be commonly associated with myelodysplastic features and a high frequency of TET2 mutations in the absence of other mutations commonly observed in AML.

Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.

Bruise-like cutaneous lesions as the early presentation of blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare and highly aggressive hematopoietic malignancy associated with a poor prognosis. It has been recognized to originate from precursors of plasmacytoid dendritic cells and has recently been established as a distinct entity. The most frequent clinical presentations are prominent skin lesions, followed by peripheral blood, bone marrow, and other organ involvement. Treatment outcomes are often disappointing due to a high relapse rate after chemotherapy and risk of leukemic dissemination. Herein, we report a case of BPDCN in a 41-year-old man who presented with cutaneous and nasopharyngeal lesions, and achieved a complete response after systemic chemotherapy. Dermatologists should be aware of BPDCN and its clinical presentations, as early diagnosis with appropriate treatment is crucial to improve its prognosis.

Narrowing down the common deleted region of 5q to 6.0 Mb in blastic plasmacytoid dendritic cell neoplasms

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy. Simple and complex recurrent cytogenetic abnormalities have been reported, which demonstrate predominantly genomic losses, of which deletions of 5q are the most frequent aberrations in BPDCN with or without cutaneous manifestation; however, the gene responsible for the disease remains unknown. Using microarray-based molecular characterization, a recent study on several cases of BPDCN with the 5q deletion identified a large, common deleted region (CDR) of 29 Mb that contains several possible candidate genes. We report on a 67-year-old female patient who presented with leukemic BPDCN without skin involvement and had a deletion of 5q and a t(6;8)(p21;q24). By oligo-array-comparative genome hybridization (a-CGH) method, the genomic coordinations of the 5q deletion demonstrated unique breakpoints reported for the first time. Through mapping with those published cases using the same a-CGH method, the CDR was reduced from 29 Mb to 6 Mb, which excluded the previous candidate genes and highlighted an excellent biological gene: the HINT1 gene. Moreover, a molecular cytogenetic characterization of the translocation t(6;8) was performed in search for a novel gene fusion that could be associated with tumor progression.

Abstract 1951: miRNA expression profile of Blastic plasmacytoid dendritic cell neoplasm.

Abstract Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare neoplasm currently included among acute myeloid leukemias in the WHO classification. BPDCN is an orphan tumor characterized by an unknown biology with clinical aggressive course and dismal prognosis. Only few studies explored its genetics, documenting a complex karyotype and sporadic genetic alterations. Unfortunately, data were based on a limited number of patients and lacked functional elucidation. Conversely, studies on the transcriptome only compared BPDCN with other leukemias, failing to identify pathogenetic events. In this study we aimed to assess whether miRNA deregulation contribute to BPDCN pathogenesis and clinical behaviour. Methods: We studied by miRNA profiling (NanoString Technologies) 30 BPDCN samples, 9 normal plasmacytoid dendritic cell (pDCs) samples and the CAL-1 tumor cell line. In addition, 25 independent BPDCN cases were studied by qRT-PCR and IHC as validation. To investigate the functional consequences of miRNA deregulation, we also performed a global gene expression profile (GEP) analysis on the same cases by using the Illumina Whole Genome DASL Assay. We applied ANOVA and Student t-test to find genes and miRNAs differentially expressed between BPDCNs and normal pDCs. The selected miRNAs were further filtered based on their predicted impact on the GEP using Linear Discriminant Analysis, Spearman correlation and Gene Set Enrichment Analysis. Finally, the functional effects of selected miRNAs were assessed ex vivo on CAL-1 cell line. Results: We found that, according to the unsupervised analysis of miRNAs, BPDCN patients have a molecular signature well distinct from their normal counterpart. The following supervised analysis identified a set of 114 miRNAs significantly deregulated whose aberrant expression might have a relevant impact on cancer-related cellular pathways. Therefore, after validating their expression in an independent set of cases, we integrated the miRNA and mRNA expression profiles on the same patients, in order to assess the functional impact of deregulated miRNAs on gene expression profile. Pathway analysis of the predicted miRNA target genes, revealed that most of them were involved in the same gene ontology category: miRNAs synergic action appeared to strongly affect the biological process of programmed cell death. We thus focused on miRNA-mRNA anti-correlations affecting the apoptotic pathway: we transfected specific mimics and inhibitors into CAL-1 cell line; we evaluated their functional impact by gene expression profile and, finally, we confirmed their relation with specific targets by Luciferase assay. In conclusion, for the first time we investigated the miRNA profile of BPDCN, defining previously uncovered molecular mechanisms underlying the pathogenesis of the disease. Specifically, we found a subset of miRNAs significantly deregulated and highly affecting the apoptotic pathway. Citation Format: Maria Rosaria Sapienza, Fabio Fuligni, Maria Antonella Laginestra, Maura Rossi, Luciano Cascione, Alessandro Laganà, Claudio Agostinelli, Maryam Etebari, Anna Gazzola, Claudia Mannu, Elena Sabattini, Francesco Bacci, Carlo Maria Croce, Stefano Aldo Pileri, Pier Paolo Piccaluga. miRNA expression profile of Blastic plasmacytoid dendritic cell neoplasm. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1951. doi:10.1158/1538-7445.AM2013-1951

Analysis of one case of adolescent blastic plasmacytoid dendritic cell neoplasm

This study was purposed to summarize the clinical characteristics and laboratorial data of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in pediatric patients in order to enhance understanding this disease in diagnosis and therapy. A rare case of BPDCN in children was enrolled in this study. The blood routine test, examination of bone marrow cell morphology, histopathology and immunophenotype of the skin lesions were performed and analysed, the single cell suspensions of the biopsied skin mass were detected by flow cytometry. The results showed that tumor cells expressed CD4, CD56, CD43 and CD123, while not expressed CD19, CD20, CD3, CD8, CD13, CD11b and myeloperoxidase (MPO). According to the clinical and laboratorial features and the results from histopathological and immunophenotype examinations, BPDCN was confirmed. It is concluded that BPDCN in children is an extremely rare hematopoietic malignancy with presenting a rapidly and fatally aggressive clinical course. The diagnosis of this disease is mainly based on the clinical presentations, pathologic and immunohistochemical features. BPDCN is a highly aggressive disease, its prognosis is very poor, its pathogenesis remans still unclear. A standard treatment protocol for BPDCN has not yet been established.

Myeloid Lineage-Associated Mutations Are Detected in Blastic Plasmacytoid Dendritic Cell Neoplasm

Abstract 5123 Background/Purpose:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare but highly aggressive hematologic malignancy that frequently presents with skin, lymph node, and leukemic disease. Since BPDCN can evolve into acute myelomonocytic leukemia (AMML) with other cases associated with monocytosis, a close relationship of BPDCN to the myelomonocytic lineage is suspected. Here we investigate the frequency of myeloid-associated DNA mutations in BPDCN using a targeted exon sequencing panel. Methods:Nine cases of BPDCN (5 skin, 1 lymph node, 3 bone marrow clot sections) were studied. All showed blastic cytomorphology; characteristic expression of CD56 and CD123; CD4 and/or TCL1 expression; and absence of definitive lymphoid, myeloid, and monocytic marker expression. AMML recurrence at 18 months, seen in 1 patient, was also assessed. Genomic DNA was extracted from formalin-fixed paraffin-embedded sections and subjected to a 161-amplicon PCR-based DNA sequencing assay that includes the commonly mutated areas of KRAS, NRAS, IDH1, IDH2, TET2, EZH2, JAK2, and ASXL1. Limited multiplex PCR and product harvesting was performed on an Access Array chip (Fluidigm). Ion adaptors were added and DNA sequencing was performed on a PGM sequencer using the 316 chip with 200 base-pair sequencing chemistry (Life Technologies). Sensitivity of mutation detection varied between 5–10%. Sequencing data were analyzed by SeqNext software (JSI MedSystems). Detected mutations were confirmed using conventional Sanger sequencing, with an approximate sensitivity of 15%, or pyrosequencing (5%). Results:Mutations in one or more of the tested genes were found in 6 of 9 patients, with unconfirmed mutations in 2 additional cases due to low-level mutations in samples with poor quality DNA. One patient with a typical BPDCN showed an IDH2 mutation (R140Q) with recurrence as AMML showing this mutation as well as a double mutation in KRAS (G12R, Q61R). Other mutations identified included 3 in ASXL1 including W608C, NRAS G12D, EZH2 C-terminal truncation, and 2 TET2indels. Conclusions:The presence of myeloid-associated mutations particularly in IDH2, TET2 and ASXL1 in cases of BPDCN is support for a relationship to the myelomonocytic lineage. The presence of shared and new mutations in the AMML recurrence in 1 patient with BPDCN further indicates a pathogenetic relationship between the two entities. Disclosures:Wang:Quest Diagnostics: Employment. Windham:Quest Diagnostics: Employment. Billouin-Frazier:Quest Diagnostics: Employment. Jones:Quest Diagnostics: Employment.

Immunophenotypic Analysis of Myeloperoxidase-Negative Leukemia Cutis and Blastic Plasmacytoid Dendritic Cell Neoplasm

Myeloid leukemia cutis (LC) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are morphologically indistinguishable malignancies that frequently manifest in the skin. Separating myeloperoxidase-negative LC from BPDCN may be particularly challenging. We identified a panel of immunohistochemical stains to distinguish myeloid LC (23 cases) from BPDCN (12 cases): myeloperoxidase, which stained 7 cases (30%) of LC and 0 cases (0%) of BPDCN; CD56, which stained 12 cases (52%) of LC and all 12 cases (100%) of BPDCN; CD4, which stained 2 cases (9%) of LC and all 12 cases (100%) of BPDCN; CD123, which stained 4 cases (17%) of LC and 10 cases (83%) of BPDCN; and Tcl-1, which stained 2 cases (9%) of LC and 9 (82%) of 11 cases of BPDCN. It is interesting that CD33 was not helpful; it stained 18 (78%) cases of LC and 11 cases (92%) of BPDCN. Our results indicate that a panel that includes CD4, CD56, CD123, and Tcl-1 can appropriately distinguish between these 2 entities.

Blastic Plasmacytoid Dendritic Cell Neoplasm : Report of Two Cases

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumor derived from the precursor of plasmacytoid dendritic cells. We describe two cases of BPDCN. In case 1, the patient presented with multiple erythema on the trunk and arms. Histopathology of a skin biopsy specimen and immunohistochemistry demonstrated that the tumor cells were small to medium-sized with a blastoid morphology and positive for CD4, CD56, CD123 and T-cell leukemia-1 (TCL-1). In case 2, the patient presented with a solitary skin nodule and rapidly developed involvement of the bone marrow and peripheral blood. Although immunohistochemistry of the infiltrating tumor cells demonstrated positivity for CD4, CD56, CD123 and TCL-1, the cells were large with a distinct nucleolus, and different from those of typical BPDCN. The atypical morphological features of BPDCN may be diagnostically problematic, and should therefore be recognized correctly.

Leukemic Manifestation of Blastic Plasmacytoid Dendritic Cell Neoplasm Lacking Skin Lesion : A Borderline Case between Acute Monocytic Leukemia

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with a poor prognosis. We encountered a unique case of BPDCN that was leukemic at presentation without skin lesion and expressed CD33 antigen. A 74-year-old man was admitted because of dyspnea. Physically, hepatosplenomegaly, but not skin lesions and superficial lymph node swelling, was noted. The white blood count was 33.6 × 10(9)/L with 19% giant abnormal cells. These cells were positive for CD4, CD86, CD123 (bright), BDCA-2, and HLA-DR, but negative for CD1a, CD3, CD11b, CD11c, CD13, CD14, CD19, CD64, and CD68. From these findings, a diagnosis of BPDCN was made. In terms of unusual expression, these tumor cells were positive for CD33 but negative for CD56. The karyotype was 47, XY, t(6;8) (p21;q24), + r. We performed combination chemotherapy (Ara-C + VP-16 + MIT), which resulted in a marked reduction of tumor cells and improvement of the dyspnea. On day 16, however, he died of sepsis due to Bacillus cereus. The clinical picture of this patient is unusual and may provide new information on the clinicopathology of BPDCN.

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation, lacking cutaneous involvement: Case series and literature review

The diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) can be challenging, owing to the absence of traditional lineage-specific markers, but is facilitated by CD4/CD56 co-expression and frequent skin involvement. Herein, we present our collective experiences with three BPDCN cases lacking cutaneous presentation and the inherent diagnostic pitfalls. Taken in context of similar historical cases, we suggest that BPDCN with “leukemic” presentation (L-BPDCN) otherwise presents no major distinguishing features and is at least as aggressive as its cutaneous-involved BPDCN counterpart.

A Case of Blastic Plasmacytoid Dendritic Cell Neoplasm Initially Mimicking Cutaneous Lupus Erythematosus

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease. The prognosis is poor in most cases with rapid progression despite administering chemotherapy. A 67-year-old man complained of skin rashes on his back and this spread to the trunk, face, arms and thighs, and he was initially diagnosed with cutaneous lupus erythematosus according to the skin biopsy. The skin rashes then became aggravated on a trial of low dose methylprednisolone for 3 months. Repeated skin biopsy revealed a diffuse infiltration of lymphoid cells with medium sized nuclei, positive for CD4 and CD56, negative for Epstein-Barr virus (EBV), indicating a diagnosis of BPDCN. Further workups confirmed stage IVA BPDCN involving the skin, multiple lymph nodes, the peripheral blood and the bone marrow. He was treated with six cycles of combination chemotherapy consisting of ifosphamide, methotrexate, etoposide, prednisolone and L-asparaginase, and he achieved a partial response. Herein we report on a rare case of BPDCN that was initially misinterpreted as cutaneous lupus erythematosus.

1411 POSTER Impact of FDG-PET for staging of pediatric solid tumours: comparison with conventional imaging modalities

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an exceedingly rare disorder categorized under acute myeloid leukemia by the World Health Organization. Phenotypically, malignant cells coexpress CD4+ and CD56+ without coexpressing common lymphoid or myeloid lineage markers. BPDCN frequently expresses CD123, TCL1, BDCA-2, and CD2AP. Restriction of CD2AP expression to plasmacytoid dendritic cells makes it a useful tool to help confirm diagnosis. Clonal complex chromosome aberrations are described in two-thirds of cases. Eighty percent of BPDCN cases present with nonspecific dermatological manifestations, prompting inclusion in the differential diagnosis of atypical skin rashes refractory to standard treatment. Prognosis is poor, with a median survival of less than 18 months. No prospective randomized data exist to define the most optimal frontline chemotherapy. Current practice considers acute myeloid leukemia-like or acute lymphoblastic leukemia–like regimens acceptable for induction treatment. Unfortunately, responses are short-lived, with second remissions difficult to achieve, underscoring the need to consider hematopoietic cell transplantation early in the disease course. Allografting, especially if offered in first remission, can result in long-term remissions. Preclinical data suggest a potential role for immunomodulatory agents in BPCDN. However, further research efforts are needed to better understand BPDCN biology and to establish evidence-based treatment algorithms that might ultimately improve overall prognosis of this disease.