Bailey.Glen at 18:47, 3 November 2023

2023-11-03T18:47:56Z

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 ==Primary Author(s)*==
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 ==Notes==
 <nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

Bailey.Glen: Created page with "==Primary Author(s)*== Hao Liu, MD and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Myeloid neoplasms/Acute myeloid leukemia ==Cancer Sub-Classification / Subtyp..."

2023-11-03T18:07:23Z

Created page with "==Primary Author(s)*== Hao Liu, MD and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Myeloid neoplasms/Acute myeloid leukemia ==Cancer Sub-Classification / Subtyp..."

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==Primary Author(s)*==

Hao Liu, MD and Daynna J. Wolff, PhD

__TOC__

==Cancer Category/Type==

Myeloid neoplasms/Acute myeloid leukemia

==Cancer Sub-Classification / Subtype==

Blastic plasmacytoid dendritic cell neoplasm (BPDCN)

==Definition / Description of Disease==

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematologic malignancy that derives from precursors of plasmacytoid dendritic cells (pDCs)<ref name=":0">Fachetti F, et al., (2017). Blastic plasmacytoid dendritic cell neoplasm, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p174-177.</ref><ref name=":1">{{Cite journal|last=Sapienza|first=Maria Rosaria|last2=Pileri|first2=Alessandro|last3=Derenzini|first3=Enrico|last4=Melle|first4=Federica|last5=Motta|first5=Giovanna|last6=Fiori|first6=Stefano|last7=Calleri|first7=Angelica|last8=Pimpinelli|first8=Nicola|last9=Tabanelli|first9=Valentina|date=2019|title=Blastic Plasmacytoid Dendritic Cell Neoplasm: State of the Art and Prospects|url=https://www.ncbi.nlm.nih.gov/pubmed/31035408|journal=Cancers|volume=11|issue=5|doi=10.3390/cancers11050595|issn=2072-6694|pmc=6562663|pmid=31035408}}</ref>.

==Synonyms / Terminology==

* Agranular CD4+ NK cell leukaemia (obsolete)<ref name=":0" />
* Blastic NK leukaemia/lymphoma (obsolete)<ref name=":0" />
* Agranular CD4+ CD56+ hematodermic neoplasm/tumor<ref name=":0" /><ref name=":1" />

==Epidemiology / Prevalence==

*BPDCN is rare, estimated to represent < 1% of all hematologic malignancies<ref name=":0" />.

*The incidence of BPDCN in the USA: 0.04 cases per 100,000 individuals<ref name=":2">{{Cite journal|last=Khoury|first=Joseph D.|date=2018|title=Blastic Plasmacytoid Dendritic Cell Neoplasm|url=https://www.ncbi.nlm.nih.gov/pubmed/30350260|journal=Current Hematologic Malignancy Reports|volume=13|issue=6|pages=477–483|doi=10.1007/s11899-018-0489-z|issn=1558-822X|pmid=30350260}}</ref>.

*BPDCN has no known racial or ethnic predilection.

*Though BPDCN can occur at any age, it more commonly occurs in elderly patients with a mean/median patient age at diagnosis of 61-67 years<ref name=":0" /><ref name=":3">{{Cite journal|last=Kerr|first=Daniel|last2=Zhang|first2=Ling|last3=Sokol|first3=Lubomir|date=2019|title=Blastic Plasmacytoid Dendritic Cell Neoplasm|url=https://www.ncbi.nlm.nih.gov/pubmed/30715612|journal=Current Treatment Options in Oncology|volume=20|issue=1|pages=9|doi=10.1007/s11864-019-0605-x|issn=1534-6277|pmid=30715612}}</ref>.

*It most often affects males, with a male-to-female ratio of 3.3:1<ref name=":0" />.

==Clinical Features==

Typical BPDCN patients may have two stages<ref name=":0" />:

o First stage: affects the skin , usually contained or indolent

o Second stage: rapid leukemic spread and multi-organ involvement that eventually leads to death<ref name=":0" />.

==Sites of Involvement==

*Multiple sites are frequently involved by BPDCN. The three most common are the skin (in 60–100% cases), followed by the bone-marrow and peripheral blood (in 60–90% of cases), and thirdly the lymph nodes (in 40–50% of cases)<ref name=":0" />.

*Upon diagnosis, the central nervous system (CNS) is also frequently found to be involved, and up to one third of patients have CNS involvement at relapse<ref name=":2" />.

==Morphologic Features==

*BPDCN is commonly characterized by a diffuse, monomorphous infiltrate of small or medium-sized blasts<ref name=":0" />.

*The morphology of the neoplastic cells is similar to lymphoblasts or myeloblasts: high N: C ratio, eccentrically located nucleus, fine chromatin, a prominent nucleolus and scant amphophilic cytoplasm<ref name=":0" />.

*Mitoses are variable in number, and the Ki-67 rate ranges from 20 to 80%<ref name=":0" />.

*Necrosis may present.

==Immunophenotype==

*BPDCN cells express CD4, CD43, CD45RA, CD56, and the pDC associated antigens, including CD123 (IL3 α chain receptor), CD303, TCL1A, CD2AP, and TCF4<ref name=":0" /><ref name=":1" /><ref name=":2" />.

*BPDCN is characterized by high expression levels of CD123 and weak expression of CD45<ref name=":0" />.

*BPDCN cells are negative for lineage-specific markers including CD3, CD19, and myeloperoxidase<ref name=":0" /><ref name=":2" />.

*BPDCN cells also do not express myeloid cell nuclear differentiation antigen (MNDA)<ref name=":2" />.

*BPDCN cells in some cases variably express CD2, CD5, CD7, CD33, CD38, CD68, CD117, HLA-DR, and TdT<ref name=":0" /><ref name=":2" />.

==Chromosomal Rearrangements (Gene Fusions)==

A recurrent balanced translocation t(6;8)(p21;q24) involving the ''MYC'' locus was exclusively identified in BPDCN<ref name=":4">{{Cite journal|last=Kubota|first=Sho|last2=Tokunaga|first2=Kenji|last3=Umezu|first3=Tomohiro|last4=Yokomizo-Nakano|first4=Takako|last5=Sun|first5=Yuqi|last6=Oshima|first6=Motohiko|last7=Tan|first7=Kar Tong|last8=Yang|first8=Henry|last9=Kanai|first9=Akinori|date=2019|title=Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm|url=https://www.ncbi.nlm.nih.gov/pubmed/30971697|journal=Nature Communications|volume=10|issue=1|pages=1653|doi=10.1038/s41467-019-09710-z|issn=2041-1723|pmc=6458132|pmid=30971697}}</ref><ref name=":5">{{Cite journal|last=Sumarriva Lezama|first=Lhara|last2=Chisholm|first2=Karen M.|last3=Carneal|first3=Eugene|last4=Nagy|first4=Alexandra|last5=Cascio|first5=Michael J.|last6=Yan|first6=Jie|last7=Chang|first7=Chung-Che|last8=Cherry|first8=Athena|last9=George|first9=Tracy I.|date=2018|title=An analysis of blastic plasmacytoid dendritic cell neoplasm with translocations involving the MYC locus identifies t(6;8)(p21;q24) as a recurrent cytogenetic abnormality|url=https://www.ncbi.nlm.nih.gov/pubmed/29884995|journal=Histopathology|volume=73|issue=5|pages=767–776|doi=10.1111/his.13668|issn=1365-2559|pmid=29884995}}</ref><ref name=":6">{{Cite journal|last=Nakamura|first=Y.|last2=Kayano|first2=H.|last3=Kakegawa|first3=E.|last4=Miyazaki|first4=H.|last5=Nagai|first5=T.|last6=Uchida|first6=Y.|last7=Ito|first7=Y.|last8=Wakimoto|first8=N.|last9=Mori|first9=S.|date=2015|title=Identification of SUPT3H as a novel 8q24/MYC partner in blastic plasmacytoid dendritic cell neoplasm with t(6;8)(p21;q24) translocation|url=https://www.ncbi.nlm.nih.gov/pubmed/25860292|journal=Blood Cancer Journal|volume=5|pages=e301|doi=10.1038/bcj.2015.26|issn=2044-5385|pmc=4450326|pmid=25860292}}</ref><ref name=":7">{{Cite journal|last=Sakamoto|first=Kana|last2=Katayama|first2=Ryohei|last3=Asaka|first3=Reimi|last4=Sakata|first4=Seiji|last5=Baba|first5=Satoko|last6=Nakasone|first6=Hideki|last7=Koike|first7=Sumie|last8=Tsuyama|first8=Naoko|last9=Dobashi|first9=Akito|date=2018|title=Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response|url=https://www.ncbi.nlm.nih.gov/pubmed/29795241|journal=Leukemia|volume=32|issue=12|pages=2590–2603|doi=10.1038/s41375-018-0154-5|issn=1476-5551|pmid=29795241}}</ref><ref name=":8">{{Cite journal|last=Boddu|first=Prajwal C.|last2=Wang|first2=Sa A.|last3=Pemmaraju|first3=Naveen|last4=Tang|first4=Zhenya|last5=Hu|first5=Shimin|last6=Li|first6=Shaoying|last7=Xu|first7=Jie|last8=Medeiros|first8=L. Jeffrey|last9=Tang|first9=Guilin|date=2018|title=8q24/MYC rearrangement is a recurrent cytogenetic abnormality in blastic plasmacytoid dendritic cell neoplasms|url=https://www.ncbi.nlm.nih.gov/pubmed/29407586|journal=Leukemia Research|volume=66|pages=73–78|doi=10.1016/j.leukres.2018.01.013|issn=1873-5835|pmid=29407586}}</ref>. The prevalence of ''MYC'' translocation in BPDCN is 5% -12%<ref name=":5" />. Rearrangements involving the ''MYC'' locus on 8q24 are associated with MYC protein overexpression and specific clinical features, including older onset age and shorter median survival<ref name=":5" />. ''RUNX2'', located on chromosome 6p21, is strongly expressed in pDCs and BPDCN cells. The t(6,8) generates mutant-allele super-enhancer of ''RUNX2'' which may increase the expression of MYC and lead to the development of BPDCN<ref name=":4" />. SUPT3H, a TATA-binding protein-associated factors (TAF)-associated protein, was identified as a novel 8q24/''MYC'' partner in BPDCN<ref name=":6" />.

{| class="wikitable"
|'''Chromosomal Rearrangement'''
|'''Genes in Fusion (5’ or 3’ Segments)'''
|'''Pathogenic Derivative'''
|'''Prevalence'''
|-
|t(6;8)(p21;q24)
|5'RUNX2 super enhancer / 5'MYC
|increased expression MYC
|5-12%<ref name=":4" /><ref name=":5" /><ref name=":6" /><ref name=":7" /><ref name=":8" /><ref name=":9">{{Cite journal|last=Leroux|first=Dominique|last2=Mugneret|first2=Francine|last3=Callanan|first3=Mary|last4=Radford-Weiss|first4=Isabelle|last5=Dastugue|first5=Nicole|last6=Feuillard|first6=Jean|last7=Le Mée|first7=Franseza|last8=Plessis|first8=Ghislaine|last9=Talmant|first9=Pascaline|date=2002|title=CD4(+), CD56(+) DC2 acute leukemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: a study of 21 cases by the Groupe Français de Cytogénétique Hématologique|url=https://www.ncbi.nlm.nih.gov/pubmed/12010820|journal=Blood|volume=99|issue=11|pages=4154–4159|doi=10.1182/blood.v99.11.4154|issn=0006-4971|pmid=12010820}}</ref>
|-
|t(8;var)(q24;var)
|? / 5'MYC
|?increased expression MYC
|
|}

==Characteristic Chromosomal Aberrations / Patterns==

*Chromosomal abnormalities are identified in the majority of BPDCN cases; about two thirds of BPDCN patients have an abnormal karyotype<ref name=":0" />.

*About 75% of BPDCN patients have a complex karyotype, which is defined by three or more abnormalities, including at least one structural abnormality<ref name=":2" />.

*Abnormalities involving the short arm of chromosome 12, the 12p13 locus which contains ''ETV6'' gene'','' are the one of the most frequent findings in BPDCN (in 64% patients)<ref name=":0" /><ref name=":2" />.

*Chromosome 6 (6q23-qter, in 50% patients) and chromosome 13 (13q13-21, in 64% patients) are also frequently involved<ref name=":0" /><ref name=":2" />.
*Six major recurrent chromosomal targets were defined in one study<ref name=":9" />. These were 5q, 12p, 13q, 6q, 15q, and 9, which were involved in 72% (5q), 64% (12p and 13q), 50% (6q), 43% (15q), and 28% (monosomy 9) of cases, respectively.

==Genomic Gain/Loss/LOH==

1).Deletion of the 9p21.3 locus<ref name=":10">{{Cite journal|last=Lezama|first=Lhara|last2=Ohgami|first2=Robert S.|date=2019|title=Expounding on the essence of epigenetic and genetic abnormalities in blastic plasmacytoid dendritic cell neoplasms|url=https://www.ncbi.nlm.nih.gov/pubmed/30930334|journal=Haematologica|volume=104|issue=4|pages=642–643|doi=10.3324/haematol.2018.211557|issn=1592-8721|pmc=6442968|pmid=30930334}}</ref>:

· Most recurrent event in cases of BPDCN

· Associated with a poor prognosis when biallelic

2). 12p13/ETV6 deletions<ref>{{Cite journal|last=Tang|first=Zhenya|last2=Li|first2=Yan|last3=Wang|first3=Wei|last4=Yin|first4=C. Cameron|last5=Tang|first5=Guilin|last6=Aung|first6=Phyu P.|last7=Hu|first7=Shimin|last8=Lu|first8=Xinyan|last9=Toruner|first9=Gokce A.|date=2018|title=Genomic aberrations involving 12p/ETV6 are highly prevalent in blastic plasmacytoid dendritic cell neoplasms and might represent early clonal events|url=https://www.ncbi.nlm.nih.gov/pubmed/30248580|journal=Leukemia Research|volume=73|pages=86–94|doi=10.1016/j.leukres.2018.09.006|issn=1873-5835|pmid=30248580}}</ref>:

· Monoallelic or biallelic

· May represent early clonal events

3). Del(5q), del(7q), del(9q), del(11q), del(12p) and del(13q) are frequently identified in BPDCN patients with myelodysplastic syndrome or acute myeloid leukemia with myelodysplasia-related changes<ref name=":2" />.

==Gene Mutations (SNV/INDEL)==

*Common gene mutations in BPDCN: ''TET2'', ''ASXL1, NRAS, ATM'', and ''NPM1''<ref name=":0" /><ref name=":2" /><ref name=":5" /><ref name=":11">{{Cite journal|last=Sapienza|first=Maria Rosaria|last2=Abate|first2=Francesco|last3=Melle|first3=Federica|last4=Orecchioni|first4=Stefania|last5=Fuligni|first5=Fabio|last6=Etebari|first6=Maryam|last7=Tabanelli|first7=Valentina|last8=Laginestra|first8=Maria Antonella|last9=Pileri|first9=Alessandro|date=2019|title=Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target|url=https://www.ncbi.nlm.nih.gov/pubmed/30381297|journal=Haematologica|volume=104|issue=4|pages=729–737|doi=10.3324/haematol.2018.202093|issn=1592-8721|pmc=6442957|pmid=30381297}}</ref>.

*Less common mutations in BPDCN: ''APC, BRAF, IDH2, KIT, KRAS, MET, MLH1, RB1, RET, TP53'', and ''VHL''<ref name=":2" />.

===Other Mutations===
==Epigenomics (Methylation)==

*Multiple mutated epigenetic modifier genes have been identified in BPDCN<ref name=":10" /><ref name=":11" />, which include those participate in:

o DNA methylation: TET2, IDH2

o Chromatin accessibility: ARID1a, CHD8, SMARCA1

o Histone modification: methylation (ASXL1, SUZ12, MLL), demethylation (KDM4D), acetylation (EP300, EP400), ubiquitination (PHC1, PHC2), dephosphorylation (EYA2) and exchange (SRCAP)<ref name=":10" /><ref name=":11" />

==Genes and Main Pathways Involved==

· BCL-2 and NF-ĸB pathways<ref name=":10" /><ref>{{Cite journal|last=Chang|first=Kung-Chao|last2=Yu-Yun Lee|first2=Julia|last3=Sakamoto|first3=Kana|last4=Baba|first4=Satoko|last5=Takeuchi|first5=Kengo|date=2019|title=Blastic plasmacytoid dendritic cell neoplasm with immunoblastoid morphology and MYC rearrangement and overexpression|url=https://www.ncbi.nlm.nih.gov/pubmed/30482401|journal=Pathology|volume=51|issue=1|pages=100–102|doi=10.1016/j.pathol.2018.09.058|issn=1465-3931|pmid=30482401}}</ref>

==Diagnostic Testing Methods==

*A dual-color TCF4/CD123 immunohistochemistry stain has been reported to have both high sensitivity and specificity for the diagnosis<ref>{{Cite journal|last=Sukswai|first=Narittee|last2=Aung|first2=Phyu P.|last3=Yin|first3=C. Cameron|last4=Li|first4=Shaoying|last5=Wang|first5=Wei|last6=Wang|first6=Sa A.|last7=Ortega|first7=Victor|last8=Lyapichev|first8=Kirill|last9=Nagarajan|first9=Priyadharsini|date=2019|title=Dual Expression of TCF4 and CD123 Is Highly Sensitive and Specific For Blastic Plasmacytoid Dendritic Cell Neoplasm|url=https://www.ncbi.nlm.nih.gov/pubmed/31261288|journal=The American Journal of Surgical Pathology|volume=43|issue=10|pages=1429–1437|doi=10.1097/PAS.0000000000001316|issn=1532-0979|pmid=31261288}}</ref>.
*Immunophenotyping showing expression of pDC antigens and no lineage specific markers is relatively specific for this entity.
*Chromosome analysis and/or copy number assessment by whole genome microarray or other technology can identify recurrent aberrations.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

*BPDCN is extremely aggressive, with a median survival of 10-19.8 months<ref name=":0" />.

*Age is an adverse impact factor for prognosis<ref name=":0" />.

*Diagnosis is usually established through skin biopsy with immunohistochemistry or flow cytometry<ref name=":3" />.

*Traditional therapeutic approaches include multi-agent chemotherapy, such as CHOP, hyper-CVAD<ref name=":1" /><ref name=":2" /><ref name=":3" />. However, the traditional chemotherapy is associated with high relapse rate and death<ref name=":12">{{Cite journal|last=Pemmaraju|first=Naveen|last2=Lane|first2=Andrew A.|last3=Sweet|first3=Kendra L.|last4=Stein|first4=Anthony S.|last5=Vasu|first5=Sumithira|last6=Blum|first6=William|last7=Rizzieri|first7=David A.|last8=Wang|first8=Eunice S.|last9=Duvic|first9=Madeleine|date=2019|title=Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm|url=https://www.ncbi.nlm.nih.gov/pubmed/31018069|journal=The New England Journal of Medicine|volume=380|issue=17|pages=1628–1637|doi=10.1056/NEJMoa1815105|issn=1533-4406|pmid=31018069}}</ref>.

*A new targeted therapy, Tagraxofusp (SL-401, ELZONRIS) was recently approved. This agent is a CD123-directed cytotoxin consisting of recombinant human interleukin-3 fused to a truncated diphtheria toxin<ref name=":1" /><ref name=":3" /><ref name=":12" />.

*For the patients in first complete remission after induction therapy, allogeneic hematopoietic stem cell transplantation (HSCT) is recommended to achieve long-term survival<ref name=":0" /><ref name=":3" />.

==Familial Forms==

==Other Information==

==Links==

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==Reference==
<references />
<references />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

HAEM4:Blastic Plasmacytoid Dendritic Cell Neoplasm - Revision history

Bailey.Glen at 18:47, 3 November 2023

Bailey.Glen: Created page with "==Primary Author(s)*== Hao Liu, MD and Daynna J. Wolff, PhD __TOC__ ==Cancer Category/Type== Myeloid neoplasms/Acute myeloid leukemia ==Cancer Sub-Classification / Subtyp..."

Bailey.Glen: Created page with "==Primary Author(s)*== Hao Liu, MD and Daynna J. Wolff, PhD TOC ==Cancer Category/Type== Myeloid neoplasms/Acute myeloid leukemia ==Cancer Sub-Classification / Subtyp..."