Blastic Plasmacytoid Dendritic Cell Neoplasm C95.-

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic neoplasm with an aggressive clinical course and poor prognosis. BPDCN is usually characterized by the early appearance of asymptomatic, macular or nodular skin lesions. Bone marrow involvement, lymphadenopathy, splenomegaly and/or cytopenias also occur to varying degrees.

Plasmacytoid dendritic cells (pDCs) are found in blood and tissues and play an important role in immune responses by mediating between the innate and adaptive immune systems. pDCs are continuously produced in the bone marrow and eventually appear as mature cells in the periphery (Reizis B 2019). By activating Toll-like receptors, pDCs secrete a number of cytokines. Type 1 interferon (IFN; mainly IFN-alpha) is the most important cytokine, but IL-6, IL-8, IL-12, tumor necrosis factor alpha and several other proinflammatory cytokines are also secreted. This in turn leads to the activation of T cells, NK cells and macrophages, which play a role in immune responses in infections and autoimmune diseases (Swiecki M et al. 2010). In addition, pDCs include other non-type 1 IFN-producing cells and differentiated cells in blood and tissues, which explains the phenotypic diversity of BPDCN. Several pathogenic mechanisms leading to the development of BPDCN have been identified and postulated. Monoallelic and biallelic 12p13/ETV6 deletions are considered an early pathogenic event (Tang Z et al.2018).

In a subset of patients, BPDCN is considered a secondary malignancy due to the presence of myeloid dysplasia. The bromodomain and extraterminal domain protein (BET) BRD4 regulates the BPDCN-specific transcriptional network, which is controlled by the E-box transcription factor (TCF4), also known as E2-2, that regulates BPDCN cells (Ceribelli M et al. 2016). TCF4 is responsible for controlling the development of committed pDCs from common dendritic cell precursors through various other transcription factors.

The dermatological findings generally show rapidly growing, deep red or bluish-red, completely asymptomatic, hemispherical, 1-10 cm large, surface-smooth papules, plaques or nodules.

A multidisciplinary approach is essential, including a hematologist, a stem cell transplant physician, a dermatologist and an experienced hematopathologist. Initial evaluation recommendations include laboratory tests such as a CBC, complete metabolic profile and lactate dehydrogenase, as well as a bone marrow biopsy with flow cytometry, cytogenetics and next-generation sequencing. Imaging with PET/CT is also recommended. A lumbar puncture with intrathecal chemotherapy is also an essential part of the initial examination.

BPDCN presents with diffuse, monomorphic blasts with irregular nuclei, fine chromatin and sparse, agranular cytoplasm. The typical skin lesions involving these cells affect the dermis and subcutaneous adipose tissue, while the epidermis is spared (free borderline). Characteristically, there is no angioinvasion or coagulative necrosis. The expression of CD4, CD56 and CD123 is the hallmark of BPDCN. Diagnosis relies heavily on the identification of this characteristic immunophenotype. In addition, other markers specific for pDCs can further confirm the diagnosis: CD303, TCF4 and TCL1.

The diagnosis is based on the histological findings!

According to WHO 2022, the diagnosis of BPDCN requires the expression of CD123 and one other pDC marker (CD123, TCL1, TCF4, CD304 and CD303) in addition to CD4 and/or CD56.

The other immunophenotypic diagnostic criteria according to WHO 2022 include the expression of any three pDC markers and the absence of all expected negative markers (MPO, lysozyme, CD3, CD14, CD19 and CD34).10,36

Karyotype and mutations: No characteristic karyotypic abnormalities are observed in BPDCN. The most common cytogenetic abnormalities include 5q, 6q, monosomy 9, 12p, 13q and 15q. The short arm of chromosome 12, locus 12p13, which contains ETV6, is the most common finding in BPDCN. In addition, around 75% of patients have a complex karyotype. In around 38 % of patients, a rearrangement of the MYC locus on 8q24 is observed, which leads to overexpression of the MYC protein (Sakamoto K et al. 2018).

Mutations in BPDCN were identified by next-generation sequencing. The mutation spectrum in BPDCN is very similar to that in myeloid neoplasms, with a high prevalence of genes such as TET2, ASXL1 (epigenetic mutations), ZRSR2, SRSF2, U2AF1 (splicing mutations), NRAS, KRAS (RAS signaling pathway) and ATM. 22,38,39 Other less common mutations include APC, BRAF, IDH1, IDH2, KIT, KRAS, MET, MLH1, RB1, RET, TP53, CDKN1B, CDKN2A and VHL.

• Acute myeloid leukemia of the skin: Clinically comparable, histologic and immunohistologic differentiation
• Metastases of solid tumors: Clinically comparable, histological and immunohistological differentiation
• Kaposi's sarcoma:
• Angiosarcoma: Clinically comparable, typical red color of the lesions; histological and immunohistological differentiation
• Kaposi's sarcoma: Clinically comparable, typical red color of the lesions; orientation in the clefts; histological and immunohistological differentiation

• Blastomycosis: Clinically comparable, nodules along the lymphatics; histologic and immunohistologic differentiation

Allogeneic stem cell transplantation (alloSCT): AlloSCT is the only potentially curative treatment for BPDCN.

Tagraxofusp (SL-401): this is a recombinant fusion protein that fuses interleukin-3 with a truncated diphtheria toxin, was the first approved CD123-targeted therapy for BPDCN, based on a phase I/II clinical trial that showed an overall response rate of 90%. It was approved by the FDA on December 21, 2018.

Other alternative therapies include:

• IMGN632 (pivekimab sunirine)
• Venetoclax (alone and in combination with hypomethylating agents)
• CAR-T cells and bispecific monoclonal antibodies.

BPDCN is a systemic disease, and even in patients with only skin symptoms, there is often subsequent systemic involvement with a poor prognosis. Therefore, surgical excision and radiotherapy, which were used in the past, are now only used in palliative care.

Nodular pDC proliferation has been shown to be associated with various myeloid neoplasms, including chronic myelomonocytic leukemia (CMML), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Proliferation of mature plasmacytoid dendritic cells (MPDCP) associated with myeloid neoplasms was listed as a differential diagnosis for BPDCN in the 2016 WHO classification and listed as a separate disease category in the 2022 WHO classification. The two main types of MPDCP are CMML with pDC expansion (pDC-CMML) and AML with pDC expansion (pDC-AML).

A 51-year-old woman presented with a three-month history of weight loss of 6 kg, fever, occasional nosebleeds and a 10 cm non-erythematous plaque. Physical examination revealed palpable lymphadenopathy in the cervical, axillary and inguinal areas without hepatomegaly or splenomegaly. Complete blood count showed a hemoglobin level of 5.2 g/dL (normal range 12.0-16.0 g/dL), a leukocyte count of 5.6 × 109/l (normal range 4.0-10, 0 × 109/l) and platelets 14 × 109/l (normal range 150-400 × 109/l). Peripheral blood examination revealed 64 % blasts of medium size with sparse cytoplasm, fine nuclear chromatin and clear nucleoli. The lactate dehydrogenase was 4942 U/L (normal range 140-280 U/L), the other biochemical test results were unremarkable. Serologic tests for HBsAg, anti-HBc, anti-HCV, anti-EBV, anti-HIV and anti-HTLV I and II were negative.

Computed tomography (CT) of the thorax showed extensive infiltration with ground-glass opacities in both lungs, parenchymal opacities with areas of bilateral confluence, interlobular septal thickening and increased volume of the hilar and mediastinal lymph nodes. Due to the rapid progression of the disease, a lung biopsy was not performed.

Skin biopsy: consistent with non-Hodgkin's lymphoma. Immunophenotypic analysis of peripheral blood cells by flow cytometry showed the presence of 75.5% blasts. These were positive for CD4, CD7, CD36, CD43, CD56, CD123, CD302, TdT and HLA-DR.

Chemotherapy with a hyper-CVAD protocol was started. During treatment, the patient developed fever associated with neutropenia, whereupon therapy with amoxicillin and clavulanate was initiated, which was later replaced by cefepime and Bactrim. The patient's condition deteriorated clinically with hemoptysis. She developed massive alveolar hemorrhage followed by refractory septic shock and died after the seventh day of chemotherapy.

1. Adimora IJ et al. (2022) Blastic plasmacytoid dendritic cell neoplasm (BPDCN): A promising future in the era of targeted therapeutics. Cancer 128:3019-3026.
2. Barros Romão CMDS et al. (2017) Blastic Plasmacytoid Dendritic Cell Neoplasm with Pulmonary Involvement and Atypical Skin Lesion. Am J Case Rep18:692-695.
3. Ceribelli M et al. (2016) A druggable TCF4- and BRD4- dependent transcriptional network sustains malignancy in blastic plasmacytoid dendritic cell neoplasm. Cancer Cell 30:764-778.
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8. Swiecki M et al. (2010) Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev 234:142-162.
9. Tang Z et al.(2018) Genomic aberrations involving 12p/ETV6 are highly prevalent in blastic plasmacytoid dendritic cell neoplasms and might represent early clonal events. Leuk Res 73:86-94.