Blastic Plasmacytoid Dendritic Cell Neoplasm

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Primary Author(s)*

Hao Liu, MD and Daynna J. Wolff, PhD

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)[1][2].

Synonyms / Terminology

  • Agranular CD4+ NK cell leukaemia (obsolete)[1]
  • Blastic NK leukaemia/lymphoma (obsolete)[1]
  • Agranular CD4+ CD56+ hematodermic neoplasm/tumor[1][2]

Epidemiology / Prevalence

  • BPDCN is rare, estimated to represent < 1% of all hematologic malignancies[1].
  • The incidence of BPDCN in the USA: 0.04 cases per 100,000 individuals[3].
  • 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[1][4].
  • It most often affects males, with a male-to-female ratio of 3.3:1[1].

Clinical Features

Typical BPDCN patients may have two stages[1]:

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[1].

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)[1].
  • 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[3].

Morphologic Features

  • BPDCN is commonly characterized by a diffuse, monomorphous infiltrate of small or medium-sized blasts[1].
  • 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[1].
  • Mitoses are variable in number, and the Ki-67 rate ranges from 20 to 80%[1].
  • 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[1][2][3].
  • BPDCN is characterized by high expression levels of CD123 and weak expression of CD45[1].
  • BPDCN cells are negative for lineage-specific markers including CD3, CD19, and myeloperoxidase[1][3].
  • BPDCN cells also do not express myeloid cell nuclear differentiation antigen (MNDA)[3].
  • BPDCN cells in some cases variably express CD2, CD5, CD7, CD33, CD38, CD68, CD117, HLA-DR, and TdT[1][3].

Chromosomal Rearrangements (Gene Fusions)

A recurrent balanced translocation t(6;8)(p21;q24) involving the MYC locus was exclusively identified in BPDCN[5][6][7][8][9]. The prevalence of MYC translocation in BPDCN is 5% -12%[6]. 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[6]. 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[5]. SUPT3H, a TATA-binding protein-associated factors (TAF)-associated protein, was identified as a novel 8q24/MYC partner in BPDCN[7].

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%[5][6][7][8][9][10]
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[1].
  • About 75% of BPDCN patients have a complex karyotype, which is defined by three or more abnormalities, including at least one structural abnormality[3].
  • 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)[1][3].
  • Chromosome 6 (6q23-qter, in 50% patients) and chromosome 13 (13q13-21, in 64% patients) are also frequently involved[1][3].
  • Six major recurrent chromosomal targets were defined in one study[10]. 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[11]:

·        Most recurrent event in cases of BPDCN

·       Associated with a poor prognosis when biallelic

2).  12p13/ETV6 deletions[12]:

·       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[3].

Gene Mutations (SNV/INDEL)

  • Common gene mutations in BPDCN: TET2, ASXL1, NRAS, ATM, and NPM1[1][3][6][13].
  • Less common mutations in BPDCN: APC, BRAF, IDH2, KIT, KRAS, MET, MLH1, RB1, RET, TP53, and VHL[3].

Other Mutations

Epigenomics (Methylation)

  • Multiple mutated epigenetic modifier genes have been identified in BPDCN[11][13], 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)[11][13]

Genes and Main Pathways Involved

·        BCL-2 and NF-ĸB pathways[11][14]

Diagnostic Testing Methods

  • A dual-color TCF4/CD123 immunohistochemistry stain has been reported to have both high sensitivity and specificity for the diagnosis[15].
  • 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[1].
  • Age is an adverse impact factor for prognosis[1].
  • Diagnosis is usually established through skin biopsy with immunohistochemistry or flow cytometry[4].
  • Traditional therapeutic approaches include multi-agent chemotherapy, such as CHOP, hyper-CVAD[2][3][4]. However, the traditional chemotherapy is associated with high relapse rate and death[16].
  • 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[2][4][16].
  • For the patients in first complete remission after induction therapy, allogeneic hematopoietic stem cell transplantation (HSCT) is recommended to achieve long-term survival[1][4].

Familial Forms

Other Information

Links

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Reference

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 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.
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  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 Khoury, Joseph D. (2018). "Blastic Plasmacytoid Dendritic Cell Neoplasm". Current Hematologic Malignancy Reports. 13 (6): 477–483. doi:10.1007/s11899-018-0489-z. ISSN 1558-822X. PMID 30350260.
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  5. 5.0 5.1 5.2 Kubota, Sho; et al. (2019). "Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm". Nature Communications. 10 (1): 1653. doi:10.1038/s41467-019-09710-z. ISSN 2041-1723. PMC 6458132. PMID 30971697.
  6. 6.0 6.1 6.2 6.3 6.4 Sumarriva Lezama, Lhara; et al. (2018). "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". Histopathology. 73 (5): 767–776. doi:10.1111/his.13668. ISSN 1365-2559. PMID 29884995.
  7. 7.0 7.1 7.2 Nakamura, Y.; et al. (2015). "Identification of SUPT3H as a novel 8q24/MYC partner in blastic plasmacytoid dendritic cell neoplasm with t(6;8)(p21;q24) translocation". Blood Cancer Journal. 5: e301. doi:10.1038/bcj.2015.26. ISSN 2044-5385. PMC 4450326. PMID 25860292.
  8. 8.0 8.1 Sakamoto, Kana; et al. (2018). "Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response". Leukemia. 32 (12): 2590–2603. doi:10.1038/s41375-018-0154-5. ISSN 1476-5551. PMID 29795241.
  9. 9.0 9.1 Boddu, Prajwal C.; et al. (2018). "8q24/MYC rearrangement is a recurrent cytogenetic abnormality in blastic plasmacytoid dendritic cell neoplasms". Leukemia Research. 66: 73–78. doi:10.1016/j.leukres.2018.01.013. ISSN 1873-5835. PMID 29407586.
  10. 10.0 10.1 Leroux, Dominique; et al. (2002). "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". Blood. 99 (11): 4154–4159. doi:10.1182/blood.v99.11.4154. ISSN 0006-4971. PMID 12010820.
  11. 11.0 11.1 11.2 11.3 Lezama, Lhara; et al. (2019). "Expounding on the essence of epigenetic and genetic abnormalities in blastic plasmacytoid dendritic cell neoplasms". Haematologica. 104 (4): 642–643. doi:10.3324/haematol.2018.211557. ISSN 1592-8721. PMC 6442968. PMID 30930334.
  12. Tang, Zhenya; et al. (2018). "Genomic aberrations involving 12p/ETV6 are highly prevalent in blastic plasmacytoid dendritic cell neoplasms and might represent early clonal events". Leukemia Research. 73: 86–94. doi:10.1016/j.leukres.2018.09.006. ISSN 1873-5835. PMID 30248580.
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  14. Chang, Kung-Chao; et al. (2019). "Blastic plasmacytoid dendritic cell neoplasm with immunoblastoid morphology and MYC rearrangement and overexpression". Pathology. 51 (1): 100–102. doi:10.1016/j.pathol.2018.09.058. ISSN 1465-3931. PMID 30482401.
  15. Sukswai, Narittee; et al. (2019). "Dual Expression of TCF4 and CD123 Is Highly Sensitive and Specific For Blastic Plasmacytoid Dendritic Cell Neoplasm". The American Journal of Surgical Pathology. 43 (10): 1429–1437. doi:10.1097/PAS.0000000000001316. ISSN 1532-0979. PMID 31261288.
  16. 16.0 16.1 Pemmaraju, Naveen; et al. (2019). "Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm". The New England Journal of Medicine. 380 (17): 1628–1637. doi:10.1056/NEJMoa1815105. ISSN 1533-4406. PMID 31018069.


Notes

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