HAEM5:Blastic plasmacytoid dendritic cell neoplasm

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes

This page was converted to the new template on 2023-12-04. The original page can be found at HAEM4:Blastic Plasmacytoid Dendritic Cell Neoplasm.

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).

Synonyms / Terminology

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

Epidemiology / Prevalence

• BPDCN is rare, estimated to represent < 1% of all hematologic malignancies.

• The incidence of BPDCN in the USA: 0.04 cases per 100,000 individuals.

• 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.

• It most often affects males, with a male-to-female ratio of 3.3:1.

Clinical Features

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Signs and Symptoms	EXAMPLE Asymptomatic (incidental finding on complete blood counts) EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE Cytopenias EXAMPLE Lymphocytosis (low level)

editv4:Clinical Features

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Typical BPDCN patients may have two stages:

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.

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).

• 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.

Morphologic Features

• BPDCN is commonly characterized by a diffuse, monomorphous infiltrate of small or medium-sized blasts.

• 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.

• Mitoses are variable in number, and the Ki-67 rate ranges from 20 to 80%.

• Necrosis may present.

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE CD1
Positive (subset)	EXAMPLE CD2
Negative (universal)	EXAMPLE CD3
Negative (subset)	EXAMPLE CD4

editv4:Immunophenotype

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• BPDCN cells express CD4, CD43, CD45RA, CD56, and the pDC associated antigens, including CD123 (IL3 α chain receptor), CD303, TCL1A, CD2AP, and TCF4.

• BPDCN is characterized by high expression levels of CD123 and weak expression of CD45.

• BPDCN cells are negative for lineage-specific markers including CD3, CD19, and myeloperoxidase.

• BPDCN cells also do not express myeloid cell nuclear differentiation antigen (MNDA).

• BPDCN cells in some cases variably express CD2, CD5, CD7, CD33, CD38, CD68, CD117, HLA-DR, and TdT.

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE t(9;22)(q34;q11.2)	EXAMPLE 3'ABL1 / 5'BCR	EXAMPLE der(22)	EXAMPLE 20% (COSMIC) EXAMPLE 30% (add reference)	Yes	No	Yes	EXAMPLE The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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

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%
t(8;var)(q24;var)	? / 5'MYC	?increased expression MYC

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

• BPDCN is extremely aggressive, with a median survival of 10-19.8 months.

• Age is an adverse impact factor for prognosis.

• Diagnosis is usually established through skin biopsy with immunohistochemistry or flow cytometry.

• Traditional therapeutic approaches include multi-agent chemotherapy, such as CHOP, hyper-CVAD. However, the traditional chemotherapy is associated with high relapse rate and death.

• 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.

• For the patients in first complete remission after induction therapy, allogeneic hematopoietic stem cell transplantation (HSCT) is recommended to achieve long-term survival.

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE 7	EXAMPLE Loss	EXAMPLE chr7:1- 159,335,973 [hg38]	EXAMPLE chr7	Yes	Yes	No	EXAMPLE Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE 8	EXAMPLE Gain	EXAMPLE chr8:1-145,138,636 [hg38]	EXAMPLE chr8	No	No	No	EXAMPLE Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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1).Deletion of the 9p21.3 locus:

·        Most recurrent event in cases of BPDCN

·       Associated with a poor prognosis when biallelic

2).  12p13/ETV6 deletions:

·       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.

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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• Chromosomal abnormalities are identified in the majority of BPDCN cases; about two thirds of BPDCN patients have an abnormal karyotype.

• About 75% of BPDCN patients have a complex karyotype, which is defined by three or more abnormalities, including at least one structural abnormality.

• 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).

• Chromosome 6 (6q23-qter, in 50% patients) and chromosome 13 (13q13-21, in 64% patients) are also frequently involved.
• Six major recurrent chromosomal targets were defined in one study. 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.

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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• Common gene mutations in BPDCN: TET2, ASXL1, NRAS, ATM, and NPM1.

• Less common mutations in BPDCN: APC, BRAF, IDH2, KIT, KRAS, MET, MLH1, RB1, RET, TP53, and VHL.

Other Mutations

Epigenomic Alterations

• Multiple mutated epigenetic modifier genes have been identified in BPDCN, 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)

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

editv4:Genes and Main Pathways Involved

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·        BCL-2 and NF-ĸB pathways

Genetic Diagnostic Testing Methods

• A dual-color TCF4/CD123 immunohistochemistry stain has been reported to have both high sensitivity and specificity for the diagnosis.
• 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.

Links

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References

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Notes

*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. *Citation of this Page: “Blastic plasmacytoid dendritic cell neoplasm”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/4/2023, https://ccga.io/index.php/HAEM5:Blastic_plasmacytoid_dendritic_cell_neoplasm.