The patient is an 81-year-old gentleman who was referred to the hematology/oncology service for worsening fatigue and skin lesions. His past medical history is significant for myelodysplastic syndrome diagnosed 5 months ago. He was symptomatically treated and followed a relatively stable course until approximately 1 month ago. At that time, he noticed multiple skin lesions over his trunk and legs, and also became increasingly fatigued with exertional dyspnea, finding himself short of breath after climbing one flight of stairs. Laboratory data were significant for 30% circulating blasts, neutropenia (ANC = 0.96/mm3), macrocytic anemia (Hgb 7.7 g/dL, MCV 109.6), and thrombocytopenia (52 × 109/L). A bone marrow biopsy was performed for further evaluation (Fig. 1).
FLOW CYTOMETRIC STUDIES
Flow cytometry was performed for CD7, CD13, CD33, CD19, CD56, CD123, CD45, CD56, CD14, CD34, CD15, CD117, HLA-DR, CD16/57, CD4, CD8, CD2, CD16, CD13, CD11b, CD36, CD64, TdT, MPO. List mode files and example analysis for the following tubes are available as Supporting Information: CD7-FITC, CD123-PE, CD45-PerCP-Cy5, CD56-APC; CD14-FITC, CD13/33-PE, CD45-PerCP-Cy5.5, CD34-APC; CD15-FITC, CD33-PE, CD117-PerCP-Cy5.5, HLA-DR-APC; CD16/57-FITC, CD7-PE, CD4-PerCP-Cy5.5, CD3-PE-Cy7, CD56-APC, CD8-APC-H7, CD2-V450, CD45-V500; CD16-FITC, CD13-PE, CD45-PerCP-Cy5.5, CD11b-APC; CD36-FITC, CD64-PE, CD45-PerCP-Cy5, CD34-APC; cytoplasmic (c) TdT-FITC, cMPO-PE, cCD3-PerCP-Cy5.5, cCD34-APC; kappa-FITC, lambda-PE, CD19-PerCP-Cy5.5, CD5-APC; CD38-FITC, CD22-PE, CD20-PerCP-Cy5.5, CD10-APC. All of the antibodies were obtained from BD Biosciences (San Jose, CA). Files were acquired with BD FACS Canto II instruments and analyzed with DIVA software (Becton Dickinson, San Jose, CA).
Flow cytometric analysis performed on the aspirate specimen revealed a blastic neoplasm with the following phenotype: dim CD45 positive, CD34 negative, CD117 negative, CD4 positive, CD7 positive, CD56 positive, CD123 positive, TdT negative, MPO negative, CD3 negative (surface and cytoplasmic), CD19 negative, CD20 negative, CD61 negative, CD41 negative, CD13 negative, CD33 negative, partially CD36 positive, CD64 negative, CD14 negative (Figs. 2 and 3). Numerous blasts (88%) were noted on aspirate smears with minimal residual maturing hematopoietic elements (Fig. 1). Sheets of immature-appearing mononuclear cells were noted on marrow biopsy, and paraffin section immunohistochemical studies confirmed that the blasts were MPO negative, CD79a negative, CD3 negative, and strongly positive for CD123, CD4, and CD56. A butyrate esterase cytochemical stain performed on the aspirate smear did not provide evidence of monocytic differentiation. The overall features were considered diagnostic of blastic plasmacytoid dendritic cell neoplasm (BPDCN). The skin lesions were also biopsied and showed involvement by BPDCN.
BPDCN is the leukemic counterpart of plasmacytoid dendritic cells (PDC) (). BPDCN is typically a disease of elderly patients, although a few pediatric cases have been reported ([2-4]). A subset of patients have a pre-existing myeloid neoplasm such as myelodysplasia, similar to this case (). Cutaneous lesions are often present at the time of diagnosis, and isolated skin lesions may be the initial presenting feature. However, BPDCN widely disseminates, and despite an initial response to systemic chemotherapy, relapses are frequent in the absence of allogeneic hematopoietic stem cell transplantation (allo-SCT). Treatment with acute myeloid leukemia (AML)-type induction chemotherapy regimens followed by allo-SCT at the first complete remission has been advocated ([4, 5]). Although the older age of the patient populations presents a challenge to the treating hematologist/oncologist, reduced-intensity conditioning allo-SCT has been shown to be effective in patients up to 70 years of age ().
However, the disease must first be correctly classified in order to enable appropriate therapy. Although BPDCN is a newly defined entity in the 2008 WHO classification, it is not a new disease, and previously had been known as “CD4+/CD56+ hematodermic neoplasm” as well as “blastic NK-cell lymphoma” ([4, 7-9]). Given that the neoplastic cells lack lineage-specific myeloid, B, or T-cell antigens, extensive immunophenotypic characterization must be employed to establish the diagnosis. The emergence of more specific PDC markers such as CD123 has made it possible to identify the PDC origin of BPDCN ().
The primary differential diagnosis is with other types of precursor myeloid or lymphoid neoplasms, and familiarity with the immunophenotypic spectrum of BPDCN is essential. The neoplastic cells are typically dim CD45 positive and may be TdT positive, compatible with blastic, immature cells ([4, 10, 11]). Although TdT expression is more commonly seen in precursor lymphoid neoplasms, in contrast to lymphoblastic leukemias, BPDCN will not exhibit lineage-specific markers such as CD3, CD19, CD79a, or cytoplasmic CD22, although expression of the T-cell associated antigens CD2 and CD7 has been reported (). Lack of CD3 and expression of CD56 may be seen in natural killer (NK) cell neoplasms; however, CD8 rather than CD4 is characteristic of NK cell neoplasms, which also typically have expression of the epsilon chain of CD3. Although BPDCN may show expression of the myeloid-associated antigen CD33, the lineage-specific marker myeloperoxidase (MPO) is negative, CD34 is not expressed, and CD117 positivity has only rarely been reported, in contrast to many AML ([2, 3]). The CD4+/CD56+ phenotype characteristic of BPDCN may overlap with monocytic AML, which can lack expression of CD34, CD117, and MPO (). In addition, CD36 and CD68 expression may be seen in both BPDCN as well as monocytic AML. In difficult cases, cytochemical staining may be a useful diagnostic adjunct, as monocytic AML should exhibit positivity for non-specific esterase (NSE) whereas BPDCN is NSE negative. Given that a subset of BPDCN will lack expression of CD4 and/or CD56, utilizing PDC-specific markers is recommended in order to establish the diagnosis. CD123 is a robust PDC marker which has been extensively studied in prior flow cytometric studies, however, may also be seen in other hematologic malignancies such as AML, lymphoblastic leukemias, and hairy cell leukemias ([13, 14]). Additional immunohistochemical antibodies for use in tissue sections have become available to help identify PDC origin, including TCL1, BDCA-2, and CD2AP ([10, 15, 16]). These studies may be useful to correlate with the results of the flow cytometric analysis.
In summary, this case is an example of BPDCN, a rare but distinctive neoplasm with an aggressive clinical course. Familiarity with the immunophenotype (CD4+, CD56+, CD123+, occasionally TdT+, lack of lineage specific markers) enables distinction from other hematopoietic neoplasms with immunophenotypic overlap, which is essential for establishing the diagnosis and ensuring appropriate therapy.
CASE 5 DIAGNOSIS: Blastic Plasmacytoid Dendritic Cell Neoplasm