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Fang Y, Wang YZ, Chen L. A neonatal case of cutaneous blastic plasmacytoid dendritic cell neoplasm with transient regression. Pediatr Blood Cancer 2024; 71:e31263. [PMID: 39118246 DOI: 10.1002/pbc.31263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 07/28/2024] [Indexed: 08/10/2024]
Affiliation(s)
- Yuan Fang
- Department of Pathology, Anhui Provincial Children's Hospital, Hefei, China
| | - Yi-Zhen Wang
- Department of Pathology, Anhui Provincial Children's Hospital, Hefei, China
| | - Lian Chen
- Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
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2
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Yin L, Yu Q, Zhang H, Zhu H, Deng Z, Xing C, Wang P, Zeng X, Cheng Z, Sheng Y, Peng H. Novel IKZF1 rearrangement identified in a patient with blastic plasmacytoid dendritic cell neoplasm decreased haematopoietic stem cell function and promoted plasmacytoid dendritic cell abnormality. Br J Haematol 2024; 204:2496-2500. [PMID: 38616623 DOI: 10.1111/bjh.19429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 03/12/2024] [Accepted: 03/15/2024] [Indexed: 04/16/2024]
Affiliation(s)
- Le Yin
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Qian Yu
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Huifang Zhang
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Hongkai Zhu
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Zeyu Deng
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Cheng Xing
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Peilong Wang
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Xiangju Zeng
- Department of Outpatient, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhao Cheng
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Yue Sheng
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
| | - Hongling Peng
- Division of Hematology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
- Institute of Molecular Hematology, Central South University, Changsha, Hunan, China
- Hunan Engineering Research Center of Cell Immunotherapy for Hematopoietic Malignancies, Changsha, Hunan, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, Changsha, Hunan, China
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3
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Schulert GS, Zhang K. Genetics of Acquired Cytokine Storm Syndromes : Secondary HLH Genetics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:103-119. [PMID: 39117810 DOI: 10.1007/978-3-031-59815-9_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Secondary hemophagocytic lymphohistiocytosis (sHLH) has historically been defined as a cytokine storm syndrome (CSS) occurring in the setting of triggers leading to strong and dysregulated immunological activation, without known genetic predilection. However, recent studies have suggested that existing underlying genetic factors may synergize with particular diseases and/or environmental triggers (including infection, autoimmune/autoinflammatory disorder, certain biologic therapies, or malignant transformation), leading to sHLH. With the recent advances in genetic testing technology, more patients are examined for genetic variations in primary HLH (pHLH)-associated genes, including through whole exome and whole genome sequencing. This expanding genetic and genomic evidence has revealed HLH as a more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Rather than a simple, binary definition of pHLH and sHLH, HLH represents a spectrum of diseases, from a severe complication of common infections (EBV, influenza) to early onset familial diseases that can only be cured by transplantation.
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Affiliation(s)
- Grant S Schulert
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Kejian Zhang
- Sema4 and Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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4
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Yang CX, Yang Y, Zhang FL, Wang DH, Bian QH, Zhou M, Zhou MX, Yang XY. Congenital leukemia: A case report and review of literature. World J Clin Cases 2023; 11:7227-7233. [PMID: 37946786 PMCID: PMC10631425 DOI: 10.12998/wjcc.v11.i29.7227] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/11/2023] [Accepted: 09/19/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Acute leukemia in newborns is also known as neonatal or congenital leukemia (CL) and is a rare disease with an incidence rate of 1-5 per 1000000 live births. After birth, infants with CL exhibit infiltrative cutaneous nodules, hepatosplenomegaly, thrombocytopenia, and immature leukocytes in the peripheral blood. These symptoms are frequently accompanied by congenital abnormalities including trisomy 21, trisomy 9, trisomy 13, or Turner syndrome. Despite significant advances in disease management, the survival rate is approximately 25% at 2 years. CASE SUMMARY Here, we document a case of trisomy 21-related acute myeloid leukemia (AML) in a female neonate. The baby was sent to the neonatal intensive care unit because of anorexia, poor responsiveness, and respiratory distress. She was diagnosed with AML based on bone marrow aspiration and immunophenotyping. Genetic sequencing identified a mutation in the GATA1 gene. After receiving the diagnosis, the parents decided against medical care for their child, and the baby died at home on day 9 after birth. CONCLUSIONS The newborn infant was diagnosed with trisomy 21-related AML. Genetic sequencing identified a mutation in the GATA1 gene. The parents abandoned medical treatment for their infant after receiving the diagnosis, and the infant died at home on the 9th day after birth.
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Affiliation(s)
- Chun-Xia Yang
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
- Clinical Medicine, Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Ying Yang
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Fen-Li Zhang
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Ding-Huan Wang
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Qiu-Han Bian
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Man Zhou
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Ming-Xiang Zhou
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Xiao-Yan Yang
- Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
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5
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A neonatal case of congenital blastic plasmacytoid dendritic cell neoplasm with KMT2C gene duplication. Ann Hematol 2023; 102:227-229. [PMID: 36348067 DOI: 10.1007/s00277-022-05022-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/25/2022] [Indexed: 11/10/2022]
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6
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Purkait S, Gupta S, Bakhshi S, Mallick S. Blastic plasmacytoid dendritic cell neoplasm: A clinicopathological diagnostic dilemma report of three cases with review of literature. J Cancer Res Ther 2022; 18:S471-S474. [PMID: 36511007 DOI: 10.4103/jcrt.jcrt_420_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic neoplasm and classified under acute myeloid leukemia. Here, we describe the clinicopathological features of three cases of BPDCN: two with classical and one uncommon immunophenotype. A-35-year-old female (case 1) presented with complaint of nasal mass and generalized lymphadenopathy. Biopsy from axillary lymph node showed infiltration by cells with scant cytoplasm which were immunopositive for LCA, CD4, CD43, and ALK1. Flowcytometry showed positivity for CD45, CD4, CD33, and CD123 while negative for rest all markers. The other two cases have classical immunophenotype. In clinical practice, nasal mass with lymphadenopathy suggests natural killer T-cell/peripheral T-cell lymphoma. Again immunohistochemical positivity for CD4, CD43, and ALK while negativity for CD3 suggests anaplastic large cell lymphoma. In this case, morphology and extensive bone marrow involvement raise the suspicion. Fowcytometry positivity for HLADR, CD123, and CD33 helps in making diagnosis.
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Affiliation(s)
- Suvendu Purkait
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Sanjeev Gupta
- Department of Laboratory Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Sameer Bakhshi
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Saumyaranjan Mallick
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
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7
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Zhang K, Wang J, Zhu Y, Liu X, Li J, Shi Z, Cao M, Li Y. Identification of Hub Genes Associated With the Development of Stomach Adenocarcinoma by Integrated Bioinformatics Analysis. Front Oncol 2022; 12:844990. [PMID: 35686089 PMCID: PMC9170954 DOI: 10.3389/fonc.2022.844990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
Objective This study was conducted in order to gain a better understanding of the molecular mechanisms of stomach adenocarcinoma (STAD), which is necessary to predict the prognosis of STAD and develop novel gene therapy strategies. Methods In this study, the gene expression profile of GSE118916 in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) was used to explore the differential co-expression genes of STAD and normal tissues. Results A total of 407 STAD samples were collected, consisting of 375 from stomach adenocarcinoma tissues and 32 from normal tissues, as well as RNA-seq count data for 19,600 genes. Forty-two differentially expressed genes were screened by weighted gene co-expression network analysis (WGCNA) and differentially expressed gene analysis. According to the functional annotation analysis of the clusterProfiler R package, these genes were analyzed for GO function enrichment, digestion (biological process), tube bottom material membrane (cell component), and oxidoreductase activity (molecular function). The KEGG pathway was enriched in gastric acid secretion and chemical carcinogenesis. In addition, Cytoscape's cytoHubba plug-in was used to identify seven hub genes (EWSR1, ESR1, CLTC, PCMT1, TP53, HUWE1, and HDAC1) in a protein-protein interaction (PPI) network consisting of 7 nodes and 11 edges. Compared with normal tissues, CLTC and TP53 genes were upregulated in stomach adenocarcinoma (P < 0.05). TP53 was expressed differently in stages II and IV, EWSR1 was expressed differently in stages II and III, and ESR1 was expressed differently in stages I-III. Among the seven hub genes, Kaplan-Meier analysis and TCGG showed that the expression levels of HDAC1 and CLTC were significantly correlated with OS in patients with stomach adenocarcinoma (P < 0.05). GEPIA2 analysis showed that ESR1 expression was closely correlated with OS and DFS in gastric adenocarcinoma (P < 0.05). Then, the expression of the genes and their correlations were revealed by the R2 Platform (http://r2.amc.nl). Finally, we collected 18 pairs of gastric mucosal tissues from normal people and cancer tissues from patients with stomach adenocarcinoma. The expression levels of the above seven hub genes and their relative protein expression were detected by RT-PCR and immunohistochemistry (IHC). The results showed that the gene and protein expression levels in stomach adenocarcinoma tissues were increased than those in the normal group. Conclusion In summary, we believe that the identified hub genes were related to the occurrence of stomach adenocarcinoma, especially the expression of ESR1, HDAC1, and CLTC genes, which are related to the prognosis and overall survival of patients and may become the potential for the future diagnosis and treatment of STAD.
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Affiliation(s)
- Kehui Zhang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jian Wang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - YingYing Zhu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaolin Liu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiacheng Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Shi
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengxing Cao
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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8
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Rakheja D, Park JY, Fernandes NJ, Watt TC, Laetsch TW, Collins RRJ. Pediatric Non-Myofibroblastic Primitive Spindle Cell Tumors with ALK Gene Rearrangements and Response to Crizotinib. Int J Surg Pathol 2022; 30:706-715. [PMID: 35164578 DOI: 10.1177/10668969221080072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We describe two poorly differentiated, non-myofibroblastic (SMA-, S100+, CD34±), spindle cell neoplasms with immunohistochemical positivity for ALK and with ALK gene rearrangements leading to PLEKHH2::ALK and CLTC::ALK fusions, respectively. ALK protein overexpression and/or gene fusions should be evaluated in poorly differentiated spindle cell neoplasms, even when there is an absence of a myofibroblastic phenotype. A positive ALK evaluation has therapeutic implications as both tumors responded to single-agent treatment with the tyrosine kinase inhibitor crizotinib.
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Affiliation(s)
- Dinesh Rakheja
- Department of Pathology, 12334University of Texas Southwestern Medical Center, Dallas, TX, USA.,Children's Health, Dallas, TX, USA
| | - Jason Y Park
- Department of Pathology, 12334University of Texas Southwestern Medical Center, Dallas, TX, USA.,Children's Health, Dallas, TX, USA
| | - Neil J Fernandes
- Children's Health, Dallas, TX, USA.,Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tanya C Watt
- Children's Health, Dallas, TX, USA.,Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Theodore W Laetsch
- Division of Oncology, 6567Children's Hospital of Philadelphia and Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Rebecca R J Collins
- Department of Pathology, 12334University of Texas Southwestern Medical Center, Dallas, TX, USA.,Children's Health, Dallas, TX, USA
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9
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Shijie L, Zhen P, Kang Q, Hua G, Qingcheng Y, Dongdong C. Deregulation of CLTC interacts with TFG, facilitating osteosarcoma via the TGF-beta and AKT/mTOR signaling pathways. Clin Transl Med 2021; 11:e377. [PMID: 34185412 PMCID: PMC8214859 DOI: 10.1002/ctm2.377] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 03/11/2021] [Accepted: 03/15/2021] [Indexed: 01/05/2023] Open
Abstract
Although the treatment of osteosarcoma has improved, the overall survival rate of this common type of osseous malignancies has not changed for four decades. Thus, new targets for better therapeutic regimens are urgently needed. In this study, we found that high expression of clathrin heavy chain (CLTC) was an independent prognostic factor for tumor-free survival (HzR, 3.049; 95% CI, 1.476-6.301) and overall survival (HzR, 2.469; 95% CI, 1.005-6.067) of patients with osteosarcoma. Down-regulation of CLTC resulted in tumor-suppressive effects in vitro and in vivo. Moreover, we found that CLTC was transcriptionally regulated by a transcription factor-specificity protein 1 (SP1), which binds to the CLTC promoter at the -320 to -314-nt and +167 to +173-nt loci. Mechanistic investigations further revealed that CLTC elicited its pro-tumor effects by directly binding to and stabilizing trafficking from the endoplasmic reticulum to the Golgi regulator (TFG). Importantly, overexpression of TFG rescued both the tumor-suppressive effect and inhibition of the TGF-β and AKT/mTOR pathways caused by CLTC down-regulation, which indicated that the activity of CLTC was TFG-dependent. Immunohistochemistry analysis confirmed that CLTC expression was positively correlated with TFG expression. These findings collectively highlight CLTC as a new prognostic biomarker for patients with osteosarcoma, and the interruption of the SP1/CLTC/TFG axis may serve as a novel therapeutic strategy for osteosarcoma.
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Affiliation(s)
- Li Shijie
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Pan Zhen
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Qin Kang
- Department of Trauma and Reconstructive SurgeryRWTH Aachen University HospitalAachenGermany
| | - Guo Hua
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Yang Qingcheng
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
| | - Cheng Dongdong
- Department of OrthopedicsShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghaiChina
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Wang B, Chen R, Wang C, Guo J, Yuan M, Chen H, Xia X, Zhong D. Identification of novel ALK fusions using DNA/RNA sequencing in immunohistochemistry / RT-PCR discordant NSCLC patients. Hum Pathol 2021; 114:90-98. [PMID: 34019866 DOI: 10.1016/j.humpath.2021.05.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/08/2021] [Accepted: 05/11/2021] [Indexed: 12/25/2022]
Abstract
Anaplastic lymphocyte kinase (ALK) rearrangement, a key oncogenic driver promoting the expression of ALK protein in tumor cells, is found in 2%-7% of patients with nonsmall cell lung cancer (NSCLC). ALK fusion is routinely determined with immunohistochemistry (IHC) or RT-PCR in many laboratories. However, there were discordant cases. In this study, we employed a hybridization-based next-generation sequencing (NGS) of DNA and RNA to explore the underlying mechanisms. FFPE tissues of 302 NSCLC tumors, which had been ALK tested with IHC and RT-PCR, were retrospectively studied, of which 18 were IHC positive, and 14 were RT-PCR positive. This resulted in 4 discordant cases, which were further analyzed with NGS. One sample failed the RNA quality control due to extensive RNA degradation. Three non-EML4-ALK fusions were identified in the 4 cases with DNA sequencing, including a CLTC-ALK fusion (EX31:EX19), a WDPCP-ALK fusion (EX14:EX20), and a novel PLB1-ALK fusion (EX6:EX20). Interestingly, two additional fusions: STRN-ALK fusion (EX3:EX20) and DCTN1-ALK fusion (EX20:EX20), were identified with RNA sequencing. The discordance of IHC/RT-PCR was mainly due to limited coverage of non-EML4-ALK fusions in the RT-PCR assay. NGS-based DNA/RNA sequencing appears to be a promising rescue technique for nonclear-cut IHC/RT-PCR cases and also offers a unique opportunity to identify novel ALK fusions.
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Affiliation(s)
- Bei Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing, 100029, China.
| | | | | | - Jia Guo
- Department of Pathology, China-Japan Friendship Hospital, Beijing, 100029, China.
| | | | - Huang Chen
- Department of Pathology, China-Japan Friendship Hospital, Beijing, 100029, China.
| | | | - Dingrong Zhong
- Department of Pathology, China-Japan Friendship Hospital, Beijing, 100029, China.
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11
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Clinicopathologic and Molecular Analysis of the TFEB Fusion Variant Reveals New Members of TFEB Translocation Renal Cell Carcinomas (RCCs): Expanding the Genomic Spectrum. Am J Surg Pathol 2020; 44:477-489. [PMID: 31764220 DOI: 10.1097/pas.0000000000001408] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Xp11 renal cell carcinoma (RCC) with different gene fusions may have different clinicopathologic features. We sought to identify variant fusions in TFEB translocation RCC. A total of 31 cases of TFEB RCCs were selected for the current study; MALAT1-TFEB fusion was identified in 25 cases (81%, 25/31) using fusion probes. The remaining 6 cases (19%, 6/31) were further analyzed by RNA sequencing and 5 of them were detected with TFEB-associated gene fusions, including 2 ACTB-TFEB, 1 EWSR1-TFEB, 1 CLTC-TFEB, and 1 potential PPP1R10-TFEB (a paracentric inversion of the TFEB gene, consistent with "negative" TFEB split FISH result, and advising a potential diagnostic pitfall in detecting TFEB gene rearrangement). Four of the 5 fusion transcripts were successfully validated by reverse transcription-polymerase chain reaction and Sanger sequencing. Morphologically, approximately one third (29%, 9/31) of TFEB RCCs showed typical biphasic morphology. The remaining two thirds of the cases (71%, 22/31) exhibited nonspecific morphology, with nested, sheet-like, or papillary architecture, resembling other types of renal neoplasms, such as clear cell RCC, Xp11 RCC, perivascular epithelioid cell tumor (PEComa), or papillary RCC. Although cases bearing a MALAT1-TFEB fusion demonstrated variable morphologies, all 9 cases featuring typical biphasic morphology were associated with MALAT1-TFEB genotype. Accordingly, typical biphasic morphology suggests MALAT1-TFEB fusion, whereas atypical morphology did not suggest the specific type of fusion. Isolated or clustered eosinophilic cells were a common feature in TFEB RCCs, which may be a useful morphology diagnostic clue for TFEB RCCs. Clinicopathologic variables assessment showed that necrosis was the only morphologic feature that correlated with the aggressive behavior of TFEB RCC (P=0.004). In summary, our study expands the genomic spectrum and the clinicopathologic features of TFEB RCCs, and highlights the challenges of diagnosis and the importance of subtyping of this tumor by combining morphology and multiple molecular techniques.
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12
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Sakamoto K, Takeuchi K. Cytogenetics of Blastic Plasmacytoid Dendritic Cell Neoplasm: Chromosomal Rearrangements and DNA Copy-Number Alterations. Hematol Oncol Clin North Am 2020; 34:523-538. [PMID: 32336417 DOI: 10.1016/j.hoc.2020.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a skin-tropic hematopoietic malignancy. Approximately 60% of cases with analyzable karyotyping results show complex karyotypes. Losses are more frequently found than copy-number gains. Recurrently deleted regions include tumor suppressor genes. No specific chromosomal abnormalities have been demonstrated in BPDCN, but genomic rearrangements involving the MYB family genes and MYC were identified. One-third of cases of BPDCN harbor the 8q24 rearrangement, most frequently with 6p21 harboring RUNX2, which is associated with immunoblastoid cytomorphology and MYC expression. MYB rearrangement is detected in 20% of patients with BPDCN. We review copy-number alterations and chromosomal rearrangements.
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Affiliation(s)
- Kana Sakamoto
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan; Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kengo Takeuchi
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan; Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Clinical Pathology Center, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
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13
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Zhang X, Sun J, Yang M, Wang L, Jin J. New perspectives in genetics and targeted therapy for blastic plasmacytoid dendritic cell neoplasm. Crit Rev Oncol Hematol 2020; 149:102928. [PMID: 32234682 DOI: 10.1016/j.critrevonc.2020.102928] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 12/26/2019] [Accepted: 03/02/2020] [Indexed: 01/12/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is one rare but clinically aggressive hematological malignancy, and it is typically characterized by skin lesion and bone marrow involvement. Diagnosis of BPDCN relies on the immunophenotype positive for four of CD4, CD56, CD123, TCL1 and BDCA-2, and commonly without the expression of MPO, cytoplasmic CD3, CD13, CD64, cytoplasmic CD79a, CD19 and CD20. Commonly, BPDCN is characterized by high CD123 expression, aberrant NF-κB activation, dependence on TCF4-/BRD4-network, and deregulated cholesterol metabolism. Under conventional therapy, the survival duration is only improved in a small number of BPDCN patients. Therefore, targeted therapy should be developed. Up to now, tagraxofusp is the leading edge and has been approved for BPDCN treatment. However, most of other targeted therapy agents were still not pushed to clinical trials for BPDCN. In this review, we emphatically discuss recent perspectives on BPDCN genetic features and developments of its targeted therapy.
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Affiliation(s)
- Xiang Zhang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Jiewen Sun
- Center Laboratory, Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
| | - Min Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Lei Wang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
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14
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Bastidas Torres AN, Cats D, Mei H, Fanoni D, Gliozzo J, Corti L, Paulli M, Vermeer MH, Willemze R, Berti E, Tensen CP. Whole-genome analysis uncovers recurrent IKZF1 inactivation and aberrant cell adhesion in blastic plasmacytoid dendritic cell neoplasm. Genes Chromosomes Cancer 2019; 59:295-308. [PMID: 31846142 PMCID: PMC7079160 DOI: 10.1002/gcc.22831] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 12/04/2019] [Accepted: 12/12/2019] [Indexed: 01/29/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematological malignancy with a poorly understood pathobiology and no effective therapeutic options. Despite a few recurrent genetic defects (eg, single nucleotide changes, indels, large chromosomal aberrations) have been identified in BPDCN, none are disease‐specific, and more importantly, none explain its genesis or clinical behavior. In this study, we performed the first high resolution whole‐genome analysis of BPDCN with a special focus on structural genomic alterations by using whole‐genome sequencing and RNA sequencing. Our study, the first to characterize the landscape of genomic rearrangements and copy number alterations of BPDCN at nucleotide‐level resolution, revealed that IKZF1, a gene encoding a transcription factor required for the differentiation of plasmacytoid dendritic cell precursors, is focally inactivated through recurrent structural alterations in this neoplasm. In concordance with the genomic data, transcriptome analysis revealed that conserved IKZF1 target genes display a loss‐of‐IKZF1 expression pattern. Furthermore, up‐regulation of cellular processes responsible for cell‐cell and cell‐ECM interactions, which is a hallmark of IKZF1 deficiency, was prominent in BPDCN. Our findings suggest that IKZF1 inactivation plays a central role in the pathobiology of the disease, and consequently, therapeutic approaches directed at reestablishing the function of this gene might be beneficial for patients.
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Affiliation(s)
| | - Davy Cats
- Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
| | - Daniele Fanoni
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Jessica Gliozzo
- Department of Dermatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Laura Corti
- Department of Dermatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marco Paulli
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maarten H Vermeer
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Rein Willemze
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Emilio Berti
- Department of Dermatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Cornelis P Tensen
- Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
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15
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Trahair T, Gifford AJ, Fordham A, Mayoh C, Fadia M, Lukeis R, Wood AC, Valvi S, Walker RD, Blackburn J, Heyer EE, Mercer TR, Barbaric D, Marshall GM, MacKenzie KL. Crizotinib and Surgery for Long-Term Disease Control in Children and Adolescents With ALK-Positive Inflammatory Myofibroblastic Tumors. JCO Precis Oncol 2019; 3:1800297. [PMID: 32914017 PMCID: PMC7446396 DOI: 10.1200/po.18.00297] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2019] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Before anaplastic lymphoma kinase (ALK) inhibitors, treatment options for ALK-positive inflammatory myofibroblastic tumors (AP-IMTs) were unsatisfactory. We retrospectively analyzed the outcome of patients with AP-IMT treated with crizotinib to document response, toxicity, survival, and features associated with relapse. METHODS The cohort comprised eight patients with AP-IMT treated with crizotinib and surgery. Outcome measures were progression-free and overall survival after commencing crizotinib, treatment-related toxicities, features associated with relapse, outcome after relapse, and outcome after ceasing crizotinib. RESULTS The median follow-up after commencing crizotinib was 3 years (range, 0.9 to 5.5 years). The major toxicity was neutropenia. All patients responded to crizotinib. Five were able to discontinue therapy without recurrence (median treatment duration, 1 year; range, 0.2 to 3.0 years); one continues on crizotinib. Two critically ill patients with initial complete response experienced relapse while on therapy. Both harbored RANBP2-ALK fusions and responded to alternative ALK inhibitors; one ultimately died as a result of progressive disease, whereas the other remains alive on treatment. Progression-free and overall survival since commencement of crizotinib is 0.75 ± 0.15% and 0.83 ± 0.15%, respectively. CONCLUSION We confirm acceptable toxicity and excellent disease control in patients with AP-IMT treated with crizotinib, which may be ceased without recurrence in most. Relapses occurred in two of three patients with RANBP2-ALK translocated IMT, which suggests that such patients require additional therapy.
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Affiliation(s)
- Toby Trahair
- Sydney Children's Hospital, Randwick, New South Wales, Australia.,Children's Cancer Institute, Sydney, New South Wales, Australia.,University of New South Wales, Sydney, New South Wales, Australia
| | - Andrew J Gifford
- Children's Cancer Institute, Sydney, New South Wales, Australia.,Prince of Wales Hospital, Randwick, New South Wales, Australia
| | | | - Chelsea Mayoh
- Children's Cancer Institute, Sydney, New South Wales, Australia
| | - Mitali Fadia
- Canberra Hospital, Garran, Australian Capital Territory, Australia.,Australian National University Medical School, Acton, Australian Capital Territory, Australia
| | - Robyn Lukeis
- St Vincent's Hospital, Darlinghurst, New South Wales, Australia
| | | | - Santosh Valvi
- Perth Children's Hospital, Perth, Western Australia, Australia
| | - Roderick D Walker
- Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | - James Blackburn
- University of New South Wales, Sydney, New South Wales, Australia.,Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Erin E Heyer
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Tim R Mercer
- University of New South Wales, Sydney, New South Wales, Australia.,Garvan Institute of Medical Research, Sydney, New South Wales, Australia.,Altius Institute for Biomedical Sciences, Seattle, WA
| | - Draga Barbaric
- Sydney Children's Hospital, Randwick, New South Wales, Australia
| | - Glenn M Marshall
- Sydney Children's Hospital, Randwick, New South Wales, Australia.,Children's Cancer Institute, Sydney, New South Wales, Australia.,University of New South Wales, Sydney, New South Wales, Australia
| | - Karen L MacKenzie
- Children's Medical Research Institute, Westmead New South Wales, Australia
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16
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Moritani K, Tauchi H, Ochi F, Yonezawa S, Takemoto K, Eguchi-Ishimae M, Eguchi M, Ishii E, Nagai K. Prolonged adrenal insufficiency after high-dose glucocorticoid in infants with leukemia. Pediatr Hematol Oncol 2018; 35:355-361. [PMID: 30457427 DOI: 10.1080/08880018.2018.1539148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Although outcomes for infant leukemia have improved recently, transient adrenal insufficiency is commonly observed during treatment, especially after glucocorticoid administration. We identified three infants with acute leukemia who suffered from prolonged adrenal insufficiency requiring long-term (from 15 to 66 months) hydrocortisone replacement. All infants showed life-threatening symptoms associated with adrenal crisis after viral infections or other stress. Severe and prolonged damage of hypothalamo-pituitary-adrenal (HPA) axis is likely to occur in early infants with leukemia, therefore routine tolerance testing to evaluate HPA axis and hydrocortisone replacement therapy are recommended for infants with leukemia to avoid life-threatening complications caused by adrenal crisis.
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Affiliation(s)
- Kyoko Moritani
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
| | - Hisamichi Tauchi
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
| | - Fumihiro Ochi
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
| | - Sachiko Yonezawa
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
| | - Koji Takemoto
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
| | | | - Mariko Eguchi
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
| | - Eiichi Ishii
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
| | - Kozo Nagai
- a Department of Pediatrics , Ehime University Graduate School of Medicine , Ehime , Japan
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17
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Affiliation(s)
- Irene Roberts
- MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine; University of Oxford, Centre for Haematology; Oxford UK
- Oxford BRC Blood Theme, NIHR Oxford Biomedical Centre; Oxford UK
- Department of Paediatrics; University of Oxford; John Radcliffe Hospital; Oxford UK
| | - Nicholas J. Fordham
- MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine; University of Oxford, Centre for Haematology; Oxford UK
| | - Anupama Rao
- Great Ormond Street Hospital for Children; London UK
| | - Barbara J. Bain
- St Mary's Hospital campus of Imperial College London; St Mary's Hospital; London UK
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18
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Blastic plasmacytoid dendritic cell neoplasm: update on therapy especially novel agents. Ann Hematol 2018; 97:563-572. [DOI: 10.1007/s00277-018-3259-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 01/23/2018] [Indexed: 12/15/2022]
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19
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Deng W, Yang M, Kuang F, Liu Y, Zhang H, Cao L, Xie M, Yang L. Blastic plasmacytoid dendritic cell neoplasm in children: A review of two cases. Mol Clin Oncol 2017; 7:709-715. [PMID: 28856005 DOI: 10.3892/mco.2017.1370] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 08/01/2017] [Indexed: 01/02/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a newly characterized, rare malignant tumor of the skin and hematopoietic system. BPDCN occurs mainly in the elderly, whereas it is rarer among children, and has variable clinical manifestations. Optimal chemotherapeutic regimens for the treatment of BPDCN have not yet been determined and this tumor has a poor prognosis. In this study, two pediatric cases of BPDCN, including a 7-year-old female and a 9-year-old male patient, diagnosed at the Xiangya Hospital of Central South University over the past 2 years, were retrospectively reviewed. Both cases exhibited multiple organ involvement, although the clinical manifestations differed; they were diagnosed with BPDCN based on the clinical manifestations, pathological and immunohistochemical findings, which included positivity for CD4, CD56 and CD123. A high-risk acute lymphocytic leukemia (ALL) chemotherapy regimen was administered to both patients. The patient in the first case achieved a complete remission, but unfortunately her parents refused follow-up treatment and she succumbed to the disease 9 months after the initial diagnosis. The second patient was treated for a total of three courses with a chemotherapy regimen including daunorubicin, cytarabine and etoposide, followed by two courses of the high-risk ALL chemotherapy regimen; unfortunately, a remission was not achieved and the patient was scheduled to receive hematopoietic stem cell transplantation. Thus, not all pediatric BPDCN patients may be able to achieve complete remission following chemotherapy with the high-risk ALL regimen, and other treatment options must be investigated in the future.
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Affiliation(s)
- Wenjun Deng
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Minghua Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Feimei Kuang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yingting Liu
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hui Zhang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Lizhi Cao
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Min Xie
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Liangchun Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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20
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Meyer C, Burmeister T, Gröger D, Tsaur G, Fechina L, Renneville A, Sutton R, Venn NC, Emerenciano M, Pombo-de-Oliveira MS, Barbieri Blunck C, Almeida Lopes B, Zuna J, Trka J, Ballerini P, Lapillonne H, De Braekeleer M, Cazzaniga G, Corral Abascal L, van der Velden VHJ, Delabesse E, Park TS, Oh SH, Silva MLM, Lund-Aho T, Juvonen V, Moore AS, Heidenreich O, Vormoor J, Zerkalenkova E, Olshanskaya Y, Bueno C, Menendez P, Teigler-Schlegel A, Zur Stadt U, Lentes J, Göhring G, Kustanovich A, Aleinikova O, Schäfer BW, Kubetzko S, Madsen HO, Gruhn B, Duarte X, Gameiro P, Lippert E, Bidet A, Cayuela JM, Clappier E, Alonso CN, Zwaan CM, van den Heuvel-Eibrink MM, Izraeli S, Trakhtenbrot L, Archer P, Hancock J, Möricke A, Alten J, Schrappe M, Stanulla M, Strehl S, Attarbaschi A, Dworzak M, Haas OA, Panzer-Grümayer R, Sedék L, Szczepański T, Caye A, Suarez L, Cavé H, Marschalek R. The MLL recombinome of acute leukemias in 2017. Leukemia 2017; 32:273-284. [PMID: 28701730 PMCID: PMC5808070 DOI: 10.1038/leu.2017.213] [Citation(s) in RCA: 506] [Impact Index Per Article: 63.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/25/2017] [Accepted: 06/21/2017] [Indexed: 12/16/2022]
Abstract
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.
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Affiliation(s)
- C Meyer
- Institute of Pharmaceutical Biology/Diagnostic Center of Acute Leukemia (DCAL), Goethe-University, Frankfurt/Main, Germany
| | - T Burmeister
- Charité-Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - D Gröger
- Charité-Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - G Tsaur
- Regional Children Hospital 1, Research Institute of Medical Cell Technologies, Pediatric Oncology and Hematology Center, Ural Federal University, Ekaterinburg, Russia
| | - L Fechina
- Regional Children Hospital 1, Research Institute of Medical Cell Technologies, Pediatric Oncology and Hematology Center, Ural Federal University, Ekaterinburg, Russia
| | - A Renneville
- Laboratory of Hematology, Biology and Pathology Center, CHRU of Lille; INSERM, UMR-S 1172, Cancer Research Institute of Lille, Lille, France
| | - R Sutton
- Children's Cancer Institute Australia, Uinversity of NSW Sydney, Sydney, New South Wales, Australia
| | - N C Venn
- Children's Cancer Institute Australia, Uinversity of NSW Sydney, Sydney, New South Wales, Australia
| | - M Emerenciano
- Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil
| | - M S Pombo-de-Oliveira
- Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil
| | - C Barbieri Blunck
- Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil
| | - B Almeida Lopes
- Pediatric Hematology-Oncology Program-Research Center, Instituto Nacional de Cancer Rio de Janeiro, Rio de Janeiro, Brazil
| | - J Zuna
- CLIP, Department of Paediatric Haematology/Oncology, Charles University Prague, 2nd Faculty of Medicine, Prague, Czech Republic
| | - J Trka
- CLIP, Department of Paediatric Haematology/Oncology, Charles University Prague, 2nd Faculty of Medicine, Prague, Czech Republic
| | - P Ballerini
- Biological Hematology, AP-HP A. Trousseau, Pierre et Marie Curie University, Paris, France
| | - H Lapillonne
- Biological Hematology, AP-HP A. Trousseau, Pierre et Marie Curie University, Paris, France
| | - M De Braekeleer
- Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Laboratoire d'Histologie, Embryologie et Cytogénétique & INSERM-U1078, Brest, France
| | - G Cazzaniga
- Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano Bicocca, Monza, Italy
| | - L Corral Abascal
- Centro Ricerca Tettamanti, Clinica Pediatrica Univ. Milano Bicocca, Monza, Italy
| | | | - E Delabesse
- CHU Purpan, Laboratoire d'Hématologie, Toulouse, France
| | - T S Park
- Department of Laboratory Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - S H Oh
- Department of Laboratory Medicine, Inje University College of Medicine, Busan, Korea
| | - M L M Silva
- Cytogenetics Department, Bone Marrow Transplantation Unit, National Cancer Institute (INCA), Rio de Janeiro, Brazil
| | - T Lund-Aho
- Laboratory of Clinical Genetics, Fimlab Laboratories, Tampere, Finland
| | - V Juvonen
- Department of Clinical Chemistry and TYKSLAB, University of Turku and Turku University Central Hospital, Turku, Finland
| | - A S Moore
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - O Heidenreich
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - J Vormoor
- The Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - E Zerkalenkova
- Dmitry Rogachev National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology, Moscow
| | - Y Olshanskaya
- Dmitry Rogachev National Scientific and Practical Center of Pediatric Hematology, Oncology and Immunology, Moscow
| | - C Bueno
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.,CIBER de Cancer (CIBERONC), ISCIII, Madrid, Spain.,Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - P Menendez
- Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.,CIBER de Cancer (CIBERONC), ISCIII, Madrid, Spain.,Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - A Teigler-Schlegel
- Department of Experimental Pathology and Cytology, Institute of Pathology, Giessen, Germany
| | - U Zur Stadt
- Center for Diagnostic, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - J Lentes
- Department of Human Genetics, Hannover Medical School, Hanover, Germany
| | - G Göhring
- Department of Human Genetics, Hannover Medical School, Hanover, Germany
| | - A Kustanovich
- Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus
| | - O Aleinikova
- Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus
| | - B W Schäfer
- Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
| | - S Kubetzko
- Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
| | - H O Madsen
- Department of Clinical Immunology, University Hospital Rigshospitalet, Copenhagen, Denmark
| | - B Gruhn
- Department of Pediatrics, Jena University Hospital, Jena, Germany
| | - X Duarte
- Department of Pediatrics, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal
| | - P Gameiro
- Hemato-Oncology Laboratory, UIPM, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal
| | - E Lippert
- Hématologie Biologique, CHU de Brest and INSERM U1078, Université de Bretagne Occidentale, Brest, France
| | - A Bidet
- Hématologie Biologique, CHU de Brest and INSERM U1078, Université de Bretagne Occidentale, Brest, France
| | - J M Cayuela
- Laboratoire d'hématologie, AP-HP Saint-Louis, Paris Diderot University, Paris, France
| | - E Clappier
- Laboratoire d'hématologie, AP-HP Saint-Louis, Paris Diderot University, Paris, France
| | - C N Alonso
- Hospital Nacional de Pediatría Prof Dr J. P. Garrahan, Servcio de Hemato-Oncología, Buenos Aires, Argentina
| | - C M Zwaan
- Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - M M van den Heuvel-Eibrink
- Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - S Izraeli
- The Chaim Sheba Medical Center, Department of Pediatric Hemato-Oncology and the Cancer Research Center, Tel Aviv, Israel.,Sackler Medical School Tel Aviv University, Tel Aviv, Israel
| | - L Trakhtenbrot
- The Chaim Sheba Medical Center, Department of Pediatric Hemato-Oncology and the Cancer Research Center, Tel Aviv, Israel.,Sackler Medical School Tel Aviv University, Tel Aviv, Israel
| | - P Archer
- Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, North Bristol NHS Trust, Bristol, UK
| | - J Hancock
- Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, North Bristol NHS Trust, Bristol, UK
| | - A Möricke
- Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany
| | - J Alten
- Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany
| | - M Schrappe
- Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany
| | - M Stanulla
- Department of Pediatrics, MHH, Hanover, Germany
| | - S Strehl
- Children's Cancer Research Institute and St Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - A Attarbaschi
- Children's Cancer Research Institute and St Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - M Dworzak
- Children's Cancer Research Institute and St Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - O A Haas
- Children's Cancer Research Institute and St Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - R Panzer-Grümayer
- Children's Cancer Research Institute and St Anna Children's Hospital, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | - L Sedék
- Department of Microbiology and Immunology, Medical University of Silesia, Zabrze, Poland
| | - T Szczepański
- Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland
| | - A Caye
- Department of Genetics, AP-HP Robert Debré, Paris Diderot University, Paris, France
| | - L Suarez
- Department of Genetics, AP-HP Robert Debré, Paris Diderot University, Paris, France
| | - H Cavé
- Department of Genetics, AP-HP Robert Debré, Paris Diderot University, Paris, France
| | - R Marschalek
- Institute of Pharmaceutical Biology/Diagnostic Center of Acute Leukemia (DCAL), Goethe-University, Frankfurt/Main, Germany
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21
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Plasmacytoid dendritic cell proliferations and neoplasms involving the bone marrow. Ann Hematol 2017; 96:765-777. [DOI: 10.1007/s00277-017-2947-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 02/03/2017] [Indexed: 12/13/2022]
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22
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Nelson KN, Peiris MN, Meyer AN, Siari A, Donoghue DJ. Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders. Trends Mol Med 2016; 23:59-79. [PMID: 27988109 DOI: 10.1016/j.molmed.2016.11.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 11/11/2016] [Accepted: 11/13/2016] [Indexed: 02/07/2023]
Abstract
Receptor tyrosine kinases (RTKs) activate various signaling pathways and regulate cellular proliferation, survival, migration, and angiogenesis. Malignant neoplasms often circumvent or subjugate these pathways by promoting RTK overactivation through mutation or chromosomal translocation. RTK translocations create a fusion protein containing a dimerizing partner fused to an RTK kinase domain, resulting in constitutive kinase domain activation, altered RTK cellular localization, upregulation of downstream signaling, and novel pathway activation. While RTK translocations in hematological malignancies are relatively rare, clinical evidence suggests that patients with these genetic abnormalities benefit from RTK-targeted inhibitors. Here, we present a timely review of an exciting field by examining RTK chromosomal translocations in hematological cancers, such as Anaplastic Lymphoma Kinase (ALK), Fibroblast Growth Factor Receptor (FGFR), Platelet-Derived Growth Factor Receptor (PDGFR), REarranged during Transfection (RET), Colony Stimulating Factor 1 Receptor (CSF1R), and Neurotrophic Tyrosine Kinase Receptor Type 3 (NTRK3) fusions, and discuss current therapeutic options.
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Affiliation(s)
- Katelyn N Nelson
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
| | - Malalage N Peiris
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
| | - April N Meyer
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA
| | - Asma Siari
- Université Joseph Fourier Grenoble, Grenoble, France
| | - Daniel J Donoghue
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA; Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
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Blastic Plasmacytoid Dendritic Cell Neoplasm in the Pediatric Population: A Case Series and Review of the Literature. Am J Dermatopathol 2016; 37:924-8. [PMID: 26588336 PMCID: PMC4894807 DOI: 10.1097/dad.0000000000000348] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive hematologic malignancy primarily found in adults, often carrying a poor prognosis. There are only 33 reported pediatric cases of BPDCN in the literature. Although standard treatment is not yet established for children, current literature recommends the use of high-risk acute lymphoblastic leukemia (ALL)–type chemotherapy. Recent studies, however, have explored the benefits of combining chemotherapy with stem-cell transplantation. Here, the authors present 2 cases of pediatric BPDCN treated with different modalities. The first case is a 13-year-old girl who presented with a 3-month history of an initially asymptomatic firm nodule on her left shin. The second case is a 15-year-old boy who presented with a 4-month history of an enlarging subcutaneous nodule on the lower leg. Immunohistochemical staining of both patients was positive for markers consistent with BPDCN. The latter patient received ALL-type therapy alone, whereas the former received ALL-type chemotherapy and stem-cell transplantation. Since initial treatment, both patients remain disease-free. These cases contribute to the limited number of pediatric BPDCN cases, thus helping to advance our knowledge toward an optimal treatment protocol for clinical remission.
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24
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Laribi K, Denizon N, Besançon A, Farhi J, Lemaire P, Sandrini J, Truong C, Ghnaya H, Baugier de Materre A. Blastic Plasmacytoid Dendritic Cell Neoplasm: From Origin of the Cell to Targeted Therapies. Biol Blood Marrow Transplant 2016; 22:1357-1367. [DOI: 10.1016/j.bbmt.2016.03.022] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 03/19/2016] [Indexed: 12/31/2022]
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Abstract
The ROS1 gene belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. A literature review identified a ROS1 fusion in 2.54% of the patients with lung adenocarcinoma and even higher frequencies in spitzoid neoplasms and inflammatory myofibroblastic tumors. At present, 26 genes were found to fuse with ROS1, some of them already known to fuse with RET and ALK. All the fusion proteins retain the ROS1 kinase domain, but rarely its transmembrane domain. Most of the partners have dimerization domains that are retained in the fusion, presumably leading to constitutive ROS1 tyrosine kinase activation. Some partners have transmembrane domains that are retained or not in the chimeric proteins. Therefore, different ROS1 fusions have distinct subcellular localization, suggesting that they may activate different substrates in vivo.
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Affiliation(s)
- Arnaud Uguen
- Faculté de Médecine et des Sciences de la Santé, Université de Brest, Brest, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.,Service d'Anatomie et Cytologie Pathologiques, Hôpital Morvan, CHRU Brest, Brest, France
| | - Marc De Braekeleer
- Faculté de Médecine et des Sciences de la Santé, Université de Brest, Brest, France.,Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.,Service de Cytogénétique et Biologie de la Reproduction, Hôpital Morvan, CHRU Brest, Brest, France
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26
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Riaz W, Zhang L, Horna P, Sokol L. Blastic plasmacytoid dendritic cell neoplasm: update on molecular biology, diagnosis, and therapy. Cancer Control 2015; 21:279-89. [PMID: 25310209 DOI: 10.1177/107327481402100404] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. Most patients with BPDCN have skin lesions and simultaneous involvement of the peripheral blood, bone marrow, and lymph nodes. METHODS A search of PubMed and Medline was conducted for English-written articles relating to BPDCN, CD4(+)CD56(+) hematodermic neoplasm, and blastic natural killer cell lymphoma. Data regarding diagnosis, prognosis, and treatment were analyzed. RESULTS BPDCN is derived from precursor plasmacytoid dendritic cells. The diagnosis of BPDCN is based on the characteristic cytology and immunophenotype of malignant cells coexpressing CD4, CD56, CD123, blood dendritic cell antigens 2 and 4, and CD2AP markers. Multiple chromosomal abnormalities and gene mutations previously reported in patients with myeloid and selected lymphoid neoplasms were identified in approximately 60% of patients with BPDCN. Prospectively controlled studies to guide treatment decisions are lacking. The overall response rate with aggressive acute lymphoblastic leukemia-type induction regimens was as high as 90%, but the durability of response was short. Median survival rates ranged between 12 and 16 months. Patients with relapsed disease may respond to L-asparaginase-containing regimens. Allogeneic hematopoietic stem cell transplantation, particularly when performed during the first remission, may produce durable remissions in selected adults. CONCLUSIONS BPDCN is a rare aggressive disease that typically affects elderly patients. The most commonly affected nonhematopoietic organ is the skin. Although BPDCN is initially sensitive to conventional chemotherapy regimens, this response is relatively short and long-term prognosis is poor. In the near future, novel targeted therapies may improve outcomes for patients with BPDCN.
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Affiliation(s)
- Wasif Riaz
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL 33612, USA.
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