A CD56− immunoblastoid variant of blastic plasmacytoid dendritic cell neoplasm

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignant hematologic neoplasm arising from plasmacytoid dendritic cells. It is a very rare tumor that constitutes less than 0.1% of all hematologic malignancies. Most patients with BPDCN present clinically with cutaneous lesions as the first sign of disease. Immunophenotypic variability with aberrant marker profiles has been reported. We report a case of a transcription factor 4 (TCF‐4) + BPDCN, with negative CD56 expression in an 85‐year‐old woman with multiple skin nodules. A punch biopsy revealed a diffuse, monomorphous, and non‐epidermotropic cell infiltrate involving the entire dermis. The infiltrate was composed of intermediate‐sized cells with immunoblastoid morphology, which is an unusual morphologic variant. The neoplastic cells were strongly positive for CD45 and co‐expressed CD4, CD123, TCF‐4, BCL‐2, and CD10. The Ki‐67 proliferative rate was very high (90%). Negative immunostains included CD56, an unusual finding in BPDCN. This case illustrates the challenges encountered in the diagnosis of this entity, particularly in unusual morphologic variants and phenotypes. The elucidation of molecular signatures and development of targeted therapies for its management have been recently introduced and differ from acute myeloid leukemias. Hence, accurate diagnosis of BPDCN is critical for dermatopathologists.


| INTRODUCTION
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignant entity arising from precursors of plasmacytoid dendritic cells and was previously known as CD56+ cutaneous hematodermic neoplasm.5][6] At the time of diagnosis, most patients show evidence of leukemic dissemination, and extramedullary organ involvement may also occur. 5,7,8Diagnosis of BPDCN can be challenging due to immunophenotypic variability with aberrant marker profiles, such as cases that do not fit the typical CD4+ CD56+ CD123+ immunophenotype or cases in which cells express markers that have classically been related to other lineages. 4Herein, we report a case of a transcription factor 4 (TCF-4) + BPDCN, with negative CD56 expression and immunoblastoid morphology in an 85-year-old woman with multiple skin nodules.

| DISCUSSION
Lack of expression of CD56 and immunoblastoid morphology are unusual findings in BPDCN, and this case illustrates the challenges encountered in the diagnosis of BPDCN in unusual morphologic and immunophenotypic variants.While BPDCN was once named CD56+ cutaneous hematodermic neoplasm, rare instances of CD56À BPDCN have since been reported in less than 8% of cases. 9In addition, the morphology in BPDCN is usually described as lymphoblastic or myeloblastic, rather than the immunoblastoid morphology seen in this case.
An immunoblastoid variant of BPDCN has been previously identified and found to be associated with MYC rearrangement, although this is a less common variant. 10e differential diagnosis for BPDCN includes cutaneous involvement by acute myeloid leukemia (leukemia cutis) or myeloid sarcoma, extranodal NK/T-cell lymphoma, primary cutaneous T-cell lymphoma, and mature plasmacytoid dendritic cell proliferations (MPDCPs).
BPDCN is often mistaken for leukemia cutis and extramedullary myeloid sarcomas, especially in cases with monocytic differentiation where CD4, CD56, and CD123 are positive. 11The lack of CD56 positivity, in this case, contributes to diagnostic challenges.In this particular case of BPDCN, acute myeloid leukemia was excluded as the neoplastic cells were negative for lysozyme, CD117, and MPO. 12 Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive malignancy often presenting with cutaneous manifestations, particularly centered in the nasal septum, oral cavity, and paranasal sinuses.Primary cutaneous gamma-delta T-cell lymphoma is often doublenegative for CD4 and CD8 (although cases that are positive for CD4 have been described), but positive for CD56.They can share with BPDCN the expression of cytotoxic markers but is always positive for CD3.In this case, the diagnosis of ENKTL and mycosis fungoides, or cutaneous gamma-delta T-cell lymphoma were excluded due to the negative CD2, CD3, CD5, and EBV staining. 12,13BPDCN must also be differentiated from MPDCPs, which often occur in patients with a  diagnosis of chronic myelomonocytic leukemia.MPDCPs are often negative for CD56, as this case was.However, unlike this case, the Ki-67 proliferation index is low in MPDCPs. 11e elucidation of molecular signatures and development of As in F I G U R E 1 Red to purple nodule on the flank.F I G U R E 2 Histopathologic findings.Monomorphous and non-epidermotrophic cell infiltrate involving the entire dermis (A and B, Â20 and Â100 H&E).most cases of BPDCN, ENKTL is positive for CD56 and is invariably associated with EBV infection (positive EBER).As cutaneous T-cell lymphomas are the most frequent hematologic malignancies present in the skin, they should always be considered as part of the differential diagnosis.Mycosis fungoides is often CD4+, and in some circumstances can have aberrant expression of CD56.In contrast to BPDCN, the diagnosis can be confirmed by the expression of multiple T-cell antigens (CD3, CD5, CD7, CD2), a feature not seen in BPDCN.

F I G U R E 3
The infiltrate is composed of intermediate-sized cells with immunoblastoid morphology (eccentric nuclei, vesicular and open chromatin, and prominent nucleoli) (A, Â200 H&E).Frequent mitotic figures are present (B, Â1000 H&E).

F I G U R E 4
Immunophenotypic findings.The neoplastic cells are positive for BCL-2 (A, Â40) and CD123 (B, Â40).
targeted therapies for BPDCN management has been recently introduced and differs from acute myeloid leukemias and other myeloid F I G U R E 5 Immunophenotypic findings.The neoplastic cells are positive for CD4 (A, Â40) and negative for CD56 (B, Â40).F I G U R E 6 Additional immunohistochemical markers.The neoplastic cells are positive for CD45 (A, Â40) and TCF-4 (B, Â40); but they are negative for MPO (C, Â40) and lysozyme (D, Â40).
neoplasms.Particularly, the use of biological therapies (the CD123/ diphteria toxin ligand, taxagrofusp and BCL-2 inhibitors, like venetoclax).Hence, accurate diagnosis of BPDCN is critical for dermatopathologists, particularly related to unusual histomorphologic and immunophenotypic variants.