Pathology of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a malignancy derived from plasmacyoid dendritic cells. ^[1] Within the 2016 World Health Organization (WHO) category of "acute myeloid leukemia and related neoplasms," the related neoplasms derive from immature cells with evidence of myeloid differentiation, or from precursors of plasmacytoid dendritic cells. ^{[2, 3]} These disorders include BPDCN (discussed in this article); transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome; and tumoral proliferation of myeloid blasts that effaces the underlying tissue architecture (myeloid sarcoma).

Definition

The precursors of plasmacytoid dendritic cells are the cells of origin for blastic plasmacytoid dendritic cell neoplasm (BPDCN), a clinically aggressive disease with a proclivity for the skin and leukemic involvement and for which no consensus currently exists regarding optimal treatment modalities. ^{[4, 5]}  Previously used terms for this disorder have included CD4+CD56+ hematodermic tumor and blastic natural killer (NK) cell lymphoma. ^{[6, 7, 8, 9, 10]}

Epidemiology

BPDCN is a rare disorder more common in male patients. ^[11]  Although BPDCN occurs more frequently in the elderly, the tumor may occur in patients of any age, including pediatric patients. ^{[3, 12]}

Frequent sites of occurrence of blastic plasmacytoid dendritic cell neoplasm (BPDCN) include the skin, as well as the peripheral blood (PB) and bone marrow (BM). The skin lesion may present as solitary or multifocal cutaneous lesions in up to 90%. ^[11]  Although only minimal or low-level peripheral blood involvement is usuallly seen at presentation, most cases eventually evolve into an overt leukemic phase. ^[11] In addition, BPDCN can coexist or develop into an acute myeloid leukemia, sometimes in evolution from an underlying myelodysplastic syndrome. ^[13]  

A diffuse infiltrate of medium-sized cells with dispersed chromatin ("blastic") is characteristic of blastic plasmacytoid dendritic cell neoplasm (BPDCN). On bone marrow aspirate smear preparations, the neoplastic cells may display cytoplasmic vacuoles that have been likened to a pearl necklace. ^[11]  In the skin, BPDCN cells infiltrate the dermis without significant epidermotrophism. In lymph nodes, the tumor cells infiltrate the interfollicular areas and medullary areas, often diffusely, whereas bone marrow evaluation may show variable degrees of infiltration ranging from sparse to significant. ^{[9, 10, 11, 13, 14, 15]}

Pathology of blastic plasmacytoid dendritic cell neoplasm (BPDCN).Skin involvement by blastic plasmacytoid dendritic cell neoplasm.

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The neoplastic cells in blastic plasmacytoid dendritic cell neoplasm (BPDCN) are typically positive for CD45, HLA-DR, CD43, CD4, CD56, and cutaneous lymphocyte-associated antigen (CLA). ^[16]  CD79a, CD33, and CD117 may also be expressed in BPDCN. ^[17] Because CD123 and CD303 are detectable in nearly all cases of BPDCN and on biopsy specimens undergoing different fixation processes, they appear to be "backbone markers" for the histopathologic confirmation of BPDCN. ^[17]

The pDC markers, CD123 (strong), TCL-1 (90% of cases), CD45RA, blood dendritic cell antigen (BCDA)-2 (expressed in more mature cases), and myxovirus A (MxA) may be detected by flow cytometric immunophenotyping (FCI) and/or immunohistochemical (IHC) staining. ^[18]  A subset of cases may demonstrate CD2 positivity, weak CD7 positivity, weak CD33 positivity, TdT positivity (up to 50% of cases), and CD68 positivity. By definition, BPDCN must lack expression of lineage-specific markers such as CD3 and myeloperoxidase.

More recently, TCF4, which regulates and drives downstream transcriptional programs in BPDCN, appears to be a highly sensitive marker for this disease and amplifies diagnostic specificity along with CDR, CD56, CD123, and TCL1. ^[1]

All cases are otherwise negative for Epstein-Barr virus (EBV) (assayed using in situ hybridization for EBV-encoded ribonucleic acid [RNA] [EBER-ISH]), B-cell, T-cell, myeloid, and natural killer (NK) cell markers, as well as for cytotoxic proteins (assayed using IHC). Granzyme B may be demonstrated by FCI, but it is negative in tissue sections. ^{[19, 20]} The neoplastic cells are also negative for nonspecific esterase and myeloperoxidase enzyme cytochemical stains. ^[21]

Extensive phenotypic characterization may be necessary, especially given the overlap with some acute myeloid leukemias, especially those with monocytic differentiation.

T-cell receptor–[gamma] (TCR γ) gene rearrangement is absent in cases of blastic plasmacytoid dendritic cell neoplasm (BPDCN). Although clonal rearrangements of the TCR genes are lacking, occasional cases with clonal or oligoclonal TCR-gamma or TCR-delta chain gene rearrangements have been reported; these rearrangements are perhaps related to the blast stage and the expression of TdT. ^{[6, 7]}

No recurrent genetic abnormality has been described, however, complex structural chromosomal abnormalities have been demonstrated, which overlap with what is seen in acute myeloid leukemia. ^[11]  By far, the most frequently observed abnormality is deletion 5q (found in up to 72% of cases), followed in order of decreasing frequency by alterations of 13q, 12p, and 6q, and by losses of chromosomes 15 and 9. ^{[8, 9, 10, 14, 22, 23]} Trisomies of chromosomes 8 and 21 and monosomy 7 are rare, in contrast with acute myeloid leukemia and myelodysplastic syndromes (MDS). ^{[24, 25]}

In one report, treatment-related BPDCN involving deletion 7q.31 was found in a patient previously treated (5-7 years ago) with systemic alkylating agents. ^[26]

A pediatric case involving a CD4-negative variant of cutaneous BPDCN with a novel PBRM1 mutation has also been described. ^[27] The patient's histologic and immunohistochemistry findings revealed a monotonous proliferation of blasts that were CD4-, CD56+, and CD123+.

The overall prognosis of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) is poor, with a median survival of 12-14 months, despite chemotherapy and/or radiation therapy. ^[11]  In a retrospective case series comprising data from 91 patients with documented BPDCN, the median overall survival was 8-12 months. ^[28]  Age appears to be an independent prognostic factor predictive of more favorable outcomes across measures (eg, initial response to therapy, likelihood of relapse, overall survival at follow-up). ^[3]

The clinical course of BPDCN is characterized by disease relapses, and a fulminant leukemic phase ultimately develops in most patients. ^[13]  With regard to inducing remission, the use of acute lymphoblastic leukemia–type chemotherapy regimens may be superior to other chemotherapy regimens (acute myeloid leukemia, lymphoma, acute lymphoblastic leukemia/lymphoma, other, or none). ^[3]

Sustained remissions have been noted in patients who receive acute leukemia-type with therapeutic regimens, including induction chemotherapy followed by allogeneic stem cell transplantation. ^{[3, 11, 15, 29, 30]}

Tagraxofusp (Elzonris), a CD123-directed cytotoxin, was approved by the US Food and Drug Administration (FDA) in 2018 and is indicated for BPDCN in adults and children aged 2 years and older. ^[31]

FDA approval was based on results from a multicenter, multicohort, open-label, single-arm, clinical trial of 47 patients with BPDCN. ^{[31, 32, 33]} Within this cohort, 32 patients were treatment naïve and 15 patients had been previously treated. Tagraxofusp was administered on days 1 to 5 of a 21-day cycle for multiple consecutive cycles. The trial was divided into three stages: stage 1 (lead-in, dose escalation), stage 2 (expansion), and stage 3 (pivotal, confirmatory). Patients were also enrolled in an additional cohort (stage 4) to enable uninterrupted access to the drug.

In the stage 3 cohort, 13 patients with treatment-naïve BPDCN were treated, and efficacy was based on the rate of complete response or clinical complete response (CR/CRc), with CRc defined as CR with residual skin abnormality not indicative of active disease. The CR/CRc rate was 53.8% (7 of 13) and the median duration of CR/CRc was not reached (range, 3.9-12.2 months). ^[32]

Serious adverse effects of tagraxofusp included capillary leak syndrome. ^[33] Other adverse effects were hepatic dysfunction, hypoalbuminemia, peripheral edema, and thrombocytopenia.