Blastic plasmacytoid dendritic cell neoplasm
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive tumour derived from the precursors of plasmacytoid dendritic cells (PDCs, also called professional type I interferon- producing cells or plasmacytoid monocytes), with a high frequency of cutaneous and bone marrow involvement and leukaemic dissemination.
【ICD-O code 】 9727/3
Blastic NK-cell lymphoma (obsolete);
agranular CD4+ NK leukaemia (obsolete);
blastic NK leukaemia/lymphoma (obsolete);
agranular CD4+ CD56+ haematodermic neoplasm/tumour
This rare form of haematological neoplasm has no known racial or ethnic predilection. The male-to-female ratio is 3.3:1. Most patients are elderly, with a mean/median patient age at diagnosis of 61-67 years, but this neoplasm can occur at any age, including in children.
There are currently no clues to the etiology of BPDCN, but its association with myelodysplastic syndrome (MDS) in some cases may suggest a related pathogenesis. There is no association with EBV.
The disease tends to involve multiple sites, most commonly the skin (involved in 64-100% of cases), followed by the bone marrow and peripheral blood (in 60-90%) and lymph node (in 40-50%).
①Skin manifestations are the most frequent clinical presentation of typical cases of BPDCN, and the diagnosis is made on skin biopsy.
② Patients usually present with asymptomatic solitary or multiple lesions. Three types of presentation are most commonly observed: an isolated (one or few) purplish nodule type (accounting for two thirds of cases), an isolated (one or few) bruise-like papule type, and a disseminated type with purplish nodules and/or papules and/or macules.
③ Isolated nodules are preferentially found on the head and lower limbs and can be > 10 cm in diameter.
④ The isolated bruise-like papule type is clinically very challenging.
⑤ The disseminated type is the most characteristic clinical presentation.
⑥ In some patients lacking skin involvement and with leukaemic presentation, the diagnosis is made based on peripheral blood or bone marrow analyses.
⑦ Regional lymphadenopathy at presentation is common (seen in 20% of cases).
⑧ Cytopenias (especially thrombocytopenia) can occur at diagnosis and in a minority of cases is severe, indicating bone marrow failure.
⑨ About 10-20% of cases of BPDCN are associated with or develop into other myeloid neoplasms, most commonly chronic myelomonocytic leukaemia, but also MDS or acute myeloid leukaemia (AML).
⑩ BPDCN must be distinguished from mature plasmacytoid dendritic cell proliferation (MPDCP), in which PDCs are morphologically mature and CD56-negative. This condition may be associated with cutaneous lesions (rash, macules or papules, and rarely nodules) together with lymph node and/or bone marrow infiltration. MPDCP is invariably associated with a myeloid disorder (most commonly chronic myelomonocytic leukaemia, MDS, or AML).
① BPDCN is characterized by a diffuse, monomorphous infiltrate of medium-sized blast cells resembling either lymphoblasts or myeloblasts.
② Nuclei have irregular contours, fine chromatin, and one to several small nucleoli.
③ The cytoplasm is usually scant and appears greyish-blue and agranular on Giemsa staining.
④ Mitoses are variable in number, and the Ki-67 proliferation index is 20-80%; angioinvasion and coagulative necrosis are absent.
⑤ In cutaneous infiltrates, the dermis is usually massively involved, with extension to the subcutaneous fat; the epidermis and adnexa are spared, with rare exceptions.
⑥ Lymph nodes are diffusely involved in the interfollicular areas and medulla, whereas B cell follicles are often spared.
⑦ Bone marrow biopsy shows either a mild interstitial infiltrate (detectable only by immunophenotyping) or massive replacement; residual haematopoietic tissue may exhibit dysplastic features, especially in megakaryocytes.
⑧ On peripheral blood and bone marrow smears, tumour cells may show cytoplasmic microvacuoles localized along the cell membrane and pseudopodia; granules and crystals are absent.
① The tumour cells express CD4, CD43, CD45RA, and CD56, as well as the PDC-associated antigens CD123 (IL3 alpha-chain receptor), CD303, TCL1A, CD2AP, and SPIB and the type I interferon-dependent molecule MX1.
② Recently, the TCF4 (E2-2) transcription factor, which is essential to drive PDCs development, was found to represent a faithful diagnostic marker for BPDCN.
③ In about 8% of cases, CD4 or CD56 is negative, which does not rule out the diagnosis if other PDC-associated antigens (in particular CD123, TCL1A, or CD303) are expressed. Tumours that have some immunophenotypic features of BPDCN may be better classified as one of the subtypes of acute leukaemia of ambiguous lineage.
④ CD68 (an antigen typically expressed strongly on normal PDCs) is detected in 50-80% of cases, in the form of small cytoplasmic dots. Of the lymphoid and myeloid-associated antigens, CD7 and CD33 are relatively commonly expressed; some cases show expression of CD2, CD5, CD36, CD38, and CD79a, whereas CD3, CD13, CD16, CD19, CD20, LAT, lysozyme, and MPO are negative.
⑤ Granzyme B, which is found in normal PDCs, has also been demonstrated on flow cytometry immunophenotyping and mRNA analysis in BPDCN, but it is typically negative on tissue sections, as are other cytotoxic molecules such as perforin and TIA1.
⑥ In addition to CD56, BPDCN may also express other antigens that are usually negative in normal PDCs, such as BCL6, IRF4, and BCL2 (with BCL2 potentially acting against tumour cell apoptosis. In addition, S100 protein is expressed in 25-30% of all cases, and even more frequently in paediatric cases。
⑦ TdT is positive in about one third of cases, with expression in 10-80% of the cells. Occasional cases express KIT (CD117). CD34 is negative on sections, but has been found by flow immunophenotyping in 17% of cases, all invariably associated with other-lineage CD34+ blasts. EBV antigens and EBV-encoded small RNA (EBER) are negative.
② 最近发现，TCF4 (E2-2)转录因子是BPDCN的一个可靠的诊断标记，它是驱动PDCs发展的关键因子。
⑤ 粒酶B在正常PDC中表达，也在流式细胞免疫分型和BPDCN 的mRNA分析中得到证实，但它在组织切片上为阴性，其他细胞毒性分子如穿孔素和TIA1也是如此。
⑦ 约1/3病例表达TdT，10～80%的细胞阳性。偶尔表达KIT （CD117）。CD34在切片上呈阴性，但在17%的病例可通过流式检测到，所有病例都与其他谱系CD34+细胞相关。EBV抗原和EBV编码的小RNA（EBER）为阴性。