Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive malignant disease with rapid systemic spread (Swerdlow et al. 2017). The disease occurs mainly in older adults, rarely children are also affected. The latter show milder clinical courses than adults (Jegalian et al. 2010). Blastic plasmacytoid dendritic cell neoplasm accounts for only about 0.4% of all haematological neoplasias (Bueno et al. 2004, Pagano et al. 2013), the exact incidence is unknown, but men are three times more likely to develop the disease than women (Swerdlow et al. 2017).

Most frequent are initially indolent courses with multiple skin lesions. The skin manifestation is sometimes accompanied by a manifestation of lymph nodes or bone marrow involvement. The extent of bone marrow infiltration varies greatly and results in cytopenia, especially thrombocytopenia (Feuillard et al. 2002, Pagano et al. 2013). Rarely do patients show symptoms as in acute leukemia with systemic involvement without skin manifestation (Rauh et al. 2012).

 

Classification of Blastic plasmacytoid dendritic cell neoplasm

Formerly assigned to acute leukemias, BPDCN is listed as a separate entity in the new WHO classification 2017. Blastic plasmacytoid dendritic cell neoplasm is associated with a clonal proliferation of immature precursors of plasmacytoid dendritic cells. Whether these are cells of the myeloid or lymphatic series has been controversially discussed for years (Sapienza et al. 2019). Blastic plasmacytoid dendritic cell neoplasm may also occur in association with other myeloid diseases (CMML, MDS and AML) as well as in therapy-associated carcinomas and lymphomas (Swerdlow et al. 2017, Pagano et al. 2013).

Blastic plasmacytoid dendritic cell neoplasm - Diagnostics

Cytomorphology

Characteristic of blastic plasmacytoid dendritic cell neoplasm is a diffuse, monomorphic infiltration of the bone marrow with lympho- or myeloblasts. There are either massive infiltrates or only a slight interstitial infiltration, which can only be detected immunologically. The remaining haematopoiesis, may show dysplastic signs, this is especially true for the megakaryocytes. In case of skin manifestation, there is mainly an infiltration of the dermis with involvement of the subcutaneous fatty tissue. Lymph node infiltrates are found in the interfollicular areas and the medulla.

Immunophenotyping

The diagnosis of  blastic plasmacytoid dendritic cell neoplasm is mainly based on the immunophenotype. An expression of CD4, CD56, CD123, BDCA-2/CD303 and TCL1 antigens is observed; CD33, CD36 as well as CD2 and CD7 are often co-expressed. Further myeloid and lymphatic markers as well as markers of immature cells are missing. Blastic plasmacytoid dendritic cell neoplasm must be differentially diagnosed from CD56-positive acute myeloid leukemia as well as from extranodal NK/T cell lymphomas, cutaneous T cell lymphomas and subcutaneous panniculitis-like T cell lymphoma.

Chromosome analysis

Blastic plasmacytoid dendritic cell neoplasm shows no disease-specific genetic changes

Chromosomal aberrations are detected in up to 66% of blastic plasmacytoid dendritic cell neoplasm (Leroux et al. 2002). Hypodiploid or complex aberrant karyotypes with 6 to 8 aberrations are frequently found (Petrella et al. 2005), but no changes specific to the disease are observed. However, the common occurrence of aberrations, which are typically found in myeloid or lymphatic neoplasias, is characteristic in one and the same cell (Leroux et al. 2002).

Often loss of chromosomal material due to deletions and unbalanced rearrangements

In a study with a total of 21 patients with blastic plasmacytoid dendritic cell neoplasm, cytogenetic aberrations were detectable in 14 patients (Leroux et al. 2002). A deletion in the long arm of chromosome 5 (5q deletion) was observed in 10 of 14 cases (72%). In 9 out of 14 patients (64%) a deletion in the short arm of chromosome 12 (12p deletion) or a loss of material of chromosome 13 due to a deletion in the long arm (13q deletion) or a monosomy 13 was observed. A deletion in the long arm of chromosome 6 (6q deletion) was found in 7 of 14 patients (50%). A deletion in the long arm of chromosome 15 (15q deletion) or a monosomy 15 was detected in 6 of the 14 patients (43%). In addition, 4 of 14 patients (28%) had monosomy 9 (Leroux et al. 2002).

Array-based copy number analyses (aCGH) confirmed the 12p deletion (12p13, CDKN1B) and the 13q loss (13q14.2, RB1; 13q11-q12, LATS2) as recurrent aberrations. In addition, deletions were also found in the long arm of chromosome 4 (4q34), in the short arm of chromosome 7 (7p12, ICZF1), in the short arm of chromosome 9 (9p21, CDKN2A/CDKN2B) and in the short arm of chromosome 17 (17p13, TP53) (Dijkman et al. 2007, Jardin et al. 2009, Lucioni et al. 2011). For 9p deletions a prognostic significance has already been demonstrated. Patients with a heterozygous deletion showed a median survival time of 26 months. In contrast, patients with a homozygous 9p deletion were shorter at 11 months and had a lower probability of survival (Lucioni et al. 2011).

Recurrent rearrangements in BPDCN affect the MYC and the MYB gene

In about 10-15% of BPDCN cases, MYC rearrangements, which often occur in the context of lymphoid neoplasia, are detectable. However, the translocation partners are usually not immunoglobulinloci (Boddu et al. 2018). In the majority of cases the translocation takes place between 8q24 (MYC) and 6p21 (SUPT3H), but other translocation partners have also been described with colocalization in the chromosomal bands: 2p12, Xq24, 3p25, and 14q32 (Nakamura et al. 2015, Tzankov et al. 2017, Sumarriva Lezama et al. 2018, Boddu et al. 2018, Sakamoto et al. 2018). The immunohistochemical evidence showed that MYC translocations are also associated with MYC expression (Sakamoto et al. 2018). Furthermore, there is a strong association between MYC rearrangement and immunoblastoid cell morphology. There is evidence that patients with blastic plasmacytoid dendritic cell neoplasm with MYC translocation are in median older at diagnosis than patients without MYC rearrangement, especially in the presence of t(6;8)(p21;q24) (Sakamoto et al. 2018, Sumarriva Lezama et al. 2018). In a retrospective analysis, a negative influence on therapy response and survival was also demonstrated (Sakamoto et al. 2018). In another small study with 16 BPDCN patients with MYC translocation, 14 of which were already described in the literature, the median survival was 11 months. 11 of the 16 patients had a t(6;8)(p21;q24). In this group the median survival was particularly short at 3 months (Sumarriva Lezama et al. 2018).

As a further recurrent rearrangement in blastic plasmacytoid dendritic cell neoplasm, translocations involving the MYB gene (6q23.3) were identified. These appear to occur particularly in the context of pediatric BPDCN, but are also found in adults (Suzuki et al. 2017, Sakamoto et al. 2018). According to the results of the study by Sakamoto et al., rearrangements of the MYC and MYB genes are mutually exclusive.

Molecular genetics

TET2, ASXL1, NRAS, NPM1 frequently affected by mutations

Molecular genetic mutations are most frequently detected in the genes TET2 (36%), ASXL1 (32%), NRAS (20%), NPM1 (20%), in genes of the IKAROS family (20%) and in ZEB2 (16%) (Menezes et al. 2014). In a study by Menezes et al., patients with mutations in genes involved in DNA methylation (TET2, TET1, IDH1, IDH2 and DNMT3A) showed a shorter survival (11 months mutated vs. 79 months wild type). Patients with mutations in genes coding for transcription factors (ETV6, HOXB9, IKAROS family, RUNX1, ZEB2) as well as mutations in TP53 and the RAS genes were grouped into a prognostic group. This group also had an unfavourable prognosis (survival 15 months mutant vs. 99 months wild type) (Menezes et al. 2014).

Prognosis of Blastic plasmacytoid dendritic cell neoplasm

Although the majority of patients initially respond to chemotherapy, relapses are very frequent and survival time is short, averaging only 12-14 months (Pagano et al. 2013, Menezenes et al. 2014).

Therapy of Blastic plasmacytoid dendritic cell neoplasm

To date, no standardized therapy for blastic plasmacytoid dendritic cell neoplasm has been established. Currently, chemotherapy protocols for both myeloid and lymphatic acute leukemias (in individual cases also analogous lymphoma protocols), possibly followed by allogeneic stem cell transplantation, are used for patients requiring intensive therapy (Aoki et al. 2015, Pagano et al. 2013, Tzankov et al. 2017, Swerdlow et al. 2017). A consolidating autologous stem cell transplantation also seems promising (Aoki et al. 2015).

Targeted approaches could expand the therapeutic arsenal for blastic plasmacytoid dendritic cell neoplasm in the future. For example, the interleukin-3 receptor (CD123) is a suitable target due to its overexpression. Tagraxofusp, a fusion protein consisting of diphtheria toxin coupled to IL3 (Frankel et al. 2014), was approved by the FDA (FDA press release 2018) after a Phase II study and also holds the European marketing authorization for the treatment of BPDCN since January 2021 (EMA 2021). Under therapy with Tagraxofusp, response rates of 90% in previously untreated blastic plasmacytoid dendritic cell neoplasm and 67% in patients with previous therapy were achieved (Pemmaraju et al. 2019).  

Gene expression and immunohistochemical analyses have shown an aberrant activation of the NF-kB signaling pathway in blastic plasmacytoid dendritic cell neoplasm. These genes, as already successfully tested ex vivo and in the xenograft mouse model, could represent a further target structure for specific therapies in the future (Sapienza et al. 2014, Phillipe et al. 2017).

In addition, hypomethylating agents as well as BET inhibitors are currently in preclinical testing (Ceribelli et al. 2016, Emadali et al. 2016, Sapienza et al. Cancer 2019 and Haematologica 2019, Lezama & Ohgami 2019), and the use of the BCL2 inhibitor Venetoclax is also being evaluated in a clinical phase I study (NCT03485547).

References

Aoki T et al. Long-term survival following autologous and allogeneic stem cell transplantation for blastic plasmacytoid dendritic cell neoplasm. Blood 2015;125(23):3559-356.

Boddu PC et al. 8q24/MYC rearrangement is a recurrent cytogenetic abnormality in blastic plasmacytoid dendritic cell neoplasms. Leuk Res. 2018;66:73-78.

Bueno C et al. Incidence and characteristics of CD4(+)/HLA DRhi dendritic cell malignancies. Haematologica 2004;89:58-69.

Ceribelli M et al. A Druggable TCF4 and BRD4 dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer Cell 2016;30(5):764–778.

Dijkman R et al. Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood 2007; 109(4):1720-1727.

EMA, European public assessment report on Elzonris, European Medicines Agency 2021. Updated on 25/01/2021; Retrieved from https://www.ema.europa.eu/en/medicines/human/EPAR/elzonris

Emadali A et al. Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms. Blood 2016;127(24):3040-3053.

FDA. Pressemitteilung: FDA approves first treatment for rare blood disease. 21. Dezember 2018; abgerufen von https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-rare-blood-disease

Feuillard J et al. Clinical and biologic features of CD4(+)CD56(+) malignancies. Blood 2002; 99(5):1556-1563.

Frankel AE et al. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood 2014;124(3):385-392.

Jardin F et al. Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+ haematodermic neoplasms and contribute to the aggressiveness of the disease. Leukemia 2009;23(4):698-707.

Jegalian AG et al. Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications. Haematologica 2010;95(11):1873-1879.

Leroux D et al. 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 2002;99(11):4154-4159.

Lezama L, Ohgami RS. Expounding on the essence of epigenetic and genetic abnormalities in blastic plasmacytoid dendritic cell neoplasms. Haematologica 2019;104(4):642-643.

Lucioni M et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood 2011;118(17):4591-4594.

Menezes J et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 2014;28(4):823-829.

Nakamura Y et al. Identification of SUPT3H as a novel 8q24/MYC partner in blastic plasmacytoid dendritic cell neoplasm with t(6;8)(p21;q24) translocation. Blood Cancer J. 2015;5(4):e301.

Pagano L et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study. Haematologica 2013;98(2):239-246.

Pemmaraju N et al. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. NEJM 2019;380:1628-1637.

Petrella T et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol 2005;M123(5):662-675.

Phillippe L et al. Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm. Haematologica 2017;102(11):1861-1868.

Rauh MJ et al. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation, lacking cutaneous involvement: Case series and literature review. Leuk Res. 2012;36(1):81-86.

Sakamoto K et al. Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response. Leukemia 2018;32(12):2590-2603.

Sapienza MR et al. Molecular profiling of blastic plasmacytoid dendritic cell neoplasm reveals a unique pattern and suggests selective sensitivity to NF-kB pathway inhibition. Leukemia 2014;28(8):1606-1616.

Sapienza MR et al. Blastic plasmacytoid dendritic cell neoplasm: genomics mark epigenetic dysregulation as a primary therapeutic target. Haematologica 2019;104(4):729-737.

Sapienza MR et al. Blastic Plasmacytoid Dendritic Cell Neoplasm: State of the Art and Prospects. Cancers (Basel) 2019;11(5):595.

Sumarriva Lezama L et al. 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 2018;73(5):767-776.

Suzuki K et al. Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm. Leukemia 2017;31(7):1629-1633.

Swerdlow SH et al. WHO classification of tumours of haematopoetic and lymphoid tissue. International Agency of Research on Cancer 2017; 4. überarbeitete Version.

Tzankov A et al. Plasmacytoid dendritic cell proliferations and neoplasms involving the bone marrow: Summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016. Ann Hematol 2017;96(5):765-777.