Blastic plasmacytoid dendritic cell neoplasm with genetic mutations in multiple epigenetic modifiers: a case report.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematodermic malignancy derived from plasmacytoid dendritic cell precursors. Despite advances in our understanding of tumor cell surface markers, the pathogenesis of BPDCN remains largely unknown. No standard or optimal treatments are available for BPDCN, and the prognosis is usually poor. We report herein a case of BPDCN that harbored multiple genetic mutations in epigenetic modifiers such as TET2 and ZRSR2. Genetic studies in patients with BPDCN may provide insights into the underlying pathogenesis, prediction of clinical prognosis, and development of better targeted therapeutics for this rare clinical entity.

Introduction

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematodermic neoplasm characterized by skin lesions and bone marrow infiltration with progression to acute leukemia.[1] Several names, including acute agranular CD4+ natural killer (NK) cell leukemia, blastic NK cell lymphoma, and agranular CD4+CD56+ hematodermic neoplasm/tumor, have been used to describe this clinical entity as our understanding of the underlying pathogenesis has increased over the last two decades.[2] Following confirmation that the tumor cells were derived from plasmacytoid dendritic cells, the current nomenclature—BPDCN—was recommended by the 2008 World Health Organization classification of myeloid neoplasms and acute leukemia, and BPDCN was listed under the category of acute myeloid leukemia and related neoplasms in 2008.[3] BPDCN was listed as its own category in the 2016 World Health Organization revision.[4] In addition to classical BPDCN, plasmacytoid dendritic cell expansion is frequently observed in patients with acute myeloid leukemia characterized by a high frequency of RUNX1 mutations.[5] CD123-targeted therapies have been developed or are in development for treatment of BPDCN.[6-8] Despite these advances, the pathogenesis of BPDCN remains elusive.[9] Pathogenic mutations in several genes have been linked to BPDCN.[10-12] Genetic studies may provide insight into the mechanisms underlying the development of BPDCN and the development of better clinical evaluation and therapeutic strategies. We report a case of BPDCN with genetic mutations in multiple epigenetic modifiers.

Case report

A 57-year-old man presented with a 5-month history of multiple nodular lesions over his neck and chest. The nodules were progressively enlarging, and the patient had a fever 2 weeks before admission. He was otherwise well but had a 30 pack-year smoking history. A physical examination on admission found multiple 1- to 2-cm violaceous nodules and reddish papules over his chest (Figure 1a and 1b). Enlarged, nontender lymph nodes up to 2 cm in diameter were palpable in the cervical, inguinal, and axillary areas. Hepatosplenomegaly was also detected by palpation. A complete blood count revealed pancytopenia (hemoglobin of 6.2 g/dL, white blood cell count of 0.45 × 109/L, and platelet count of 8.0 × 109/L) with an increased percentage (53.3%) of lymphocytes. Computed tomography (CT) scans showed multiple pulmonary and mediastinal nodules (Figure 1c) and hepatosplenomegaly with enlarged intra-abdominal lymph nodes (Figure 1d). A lymph node biopsy showed that the tumor cells were positive for CD4, CD56, and CD123. A bone marrow aspirate demonstrated markedly hypercellular marrow with blasts accounting for 89.5% of the nucleated cells. Cytochemical staining revealed that the cells were negative for peroxidase. Flow cytometry of the bone marrow sample revealed 73.8% blasts within the nuclear cell gate. The blasts were positive for CD123, CD38, CD33, CD56, CD303, CD304, HLA-DR, cell leukemia/lymphoma protein 1 (TCL1), and terminal deoxynucleotidyl transferase (TdT), and negative for CD4 and CD13. Chromosome analysis showed a normal male karyotype (46,XY). On the basis of these findings, the patient was diagnosed with BPDCN. Next-generation sequencing of DNA from bone marrow cells showed multiple genetic mutations in epigenetic modifiers, including mutations in NRAS (p.G12D), TET2 (p.C237X and p.K1422S), NOTCH2 (p.N319S), SMC3 (p.E688Q), and ZRSR2 (p.G268D) (Table 1).

Figure 1.

Cutaneous lesions and images of the patient with blastic plasmacytoid dendritic cell neoplasm (BPDCN) Multiple cutaneous nodules and papules were observed over the chest (a) and around the armpits (b). High-resolution computed tomography images showed multiple pulmonary and mediastinal nodules (c) and enlarged intra-abdominal lymph nodes (d).

Table 1.

Hot-spot mutation sites closely related to blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Gene	Transcript	Protein change	SNP accession no.	Frequency (%)
NRAS	NM_002524	p.G12D	rs121913237	30.8
TET2	NM_001127208	p.C237X	–	47.1
TET2	NM_001127208	p.K1422Sfs*3	–	46.9
NOTCH2	NM_024408	p.N319S	rs144936899	48.6
SMC3	NM_005445	p.E688Q	rs201162818	49.3
ZRSR2	NM_005089	p.G268D	–	80.9

Transcript numbers refer to GenBank sequences (https://www.ncbi.nlm.nih.gov/).

The patient received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (CHOP), which eliminated most of the skin papules and shrank the cutaneous nodules and lymph nodes. The serum level of lactate dehydrogenase decreased from 261.82 U/L at admission to 193.5 U/L (within the reference range: 80–248 U/L). Treatment also reduced the liver and spleen enlargement, and the patient was discharged. A CT scan performed 1 month after discharge, following development of a limb movement disorder, found multiple intracranial masses, indicating invasion of the central nervous system. The patient refused further treatment and died 1 month later.

Discussion

BPDCN is an exceedingly rare aggressive hematodermic neoplasm that usually occurs in elderly patients.[13] The tumor cells of BPDCN are often positive for CD4, CD56, CD43, CD7, CD68, CD2, and HLA-DR.[14] BPDCN tumor cells are also usually positive for plasmacytoid dendritic cell-specific surface markers such as CD123, CD303, and CD304.[15] Overexpression of plasmacytoid dendritic cell markers, especially CD303, is valuable for the differential diagnosis. Although the origin and surface biomarkers of BPDCN tumor cells are well established, the underlying pathogenesis remains unclear.

Recently, the genetic mutations associated with BPDCN have received increasing attention.[15] Previous studies showed that patients with BPDCN often have complex karyotypes and chromosomal aberrations, including abnormalities in chromosome regions 5q, 12p13, 13q21, and 6q23-ter.[11,16] Genetic studies have reported that inactivation of tumor suppressors (RB1, TP53, CDKN1B, and CDKN2A), activation of oncogenes (KRAS, NRAS, HES6, RUNX2, and FLT3), and mutations in epigenetic modifiers (TET2, TET1, DNMT3A, IDH1, and IDH2) are frequently observed in BPDCN.[10,16-19] Our patient had a normal karyotype but mutations in multiple epigenetic modifiers, including NRAS, TET2, NOTCH2, SMC3, and ZRSR2. This mutational pattern supports a myeloid lineage derivation of this neoplasm.[20] As reported in previous studies,[17] TET2 and ZRSR2 are the most mutated genes in BPDCN. An epigenetic modifier, TET2 encodes the protein Tet methylcytosine dioxygenase 2, which catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine.[16] Imbalance between DNA methylation and demethylation may contribute to the development of BPDCN.

BPDCN has no uniform or standard treatment. CHOP was chosen for this patient on basis of the clinical presentation and comorbidities. The patient initially responded well to the treatment, but relapse occurred quickly after discharge. Mutations in DNA methylation genes indicate a poor prognosis in patients with BPDCN.[10] In our case, mutations in multiple genetic modifier genes likely contributed to the patient’s poor prognosis and short survival.

Mutations in genetic modifiers are not only useful to predict prognosis but also to help in development of targeted therapeutics. Deletion of TET2 leads to a dramatic reduction in the 5-hydroxymethylcytosine levels and a concomitant increase in 5-methylcytosine.[21] The hypomethylating agents azacytidine and decitabine have been shown to inhibit disease progression and improve survival in models of BPDCN.[22] Several clinical trials have found that hypomethylating agents achieved promising clinical outcomes in relapsed or refractory patients with BPDCN.[23-25] Therefore, hypomethylating agents might be a better choice for BPDCN patients harboring mutations in TET2.

In conclusion, we report a case of BPDCN that was associated with mutations in multiple epigenetic modifiers. Genetic studies on BPDCN may provide insights into the underlying pathogenesis, prediction of clinical prognosis, and development of better targeted therapeutics for this rare clinical entity.