Case Study Interpretation—New Orleans: Case 5

Christine G. Roth* and Lisa J. RobinsonDivision of Hematopathology, Department of Pathology, University of Pittsburgh School of Medicine,

Pittsburgh, Pennsylvania

Key terms: blastic plasmacytic dendritic cell neoplasm; flow cytometry; acute leukemia; CD123; CD4þ/CD56þ

Roth CG, Robinson LJ. Case study interpretation—New Orleans: Case 5. Cytometry Part B 2012; 00B: 000–000.

CASE HISTORY

The patient is an 81-year-old gentleman who wasreferred to the hematology/oncology service for worsen-ing fatigue and skin lesions. His past medical history issignificant for myelodysplastic syndrome diagnosed 5months ago. He was symptomatically treated and fol-lowed a relatively stable course until approximately 1month ago. At that time, he noticed multiple skinlesions over his trunk and legs, and also became increas-ingly fatigued with exertional dyspnea, finding himselfshort of breath after climbing one flight of stairs. Labora-tory data were significant for 30% circulating blasts, neu-tropenia (ANC ¼ 0.96/mm3), macrocytic anemia (Hgb7.7 g/dL, MCV 109.6), and thrombocytopenia (52 �109/L). A bone marrow biopsy was performed for fur-ther 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 filesand example analysis for the following tubes are availableas 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 wereobtained from BD Biosciences (San Jose, CA). Files were

acquired with BD FACS Canto II instruments and analyzedwith DIVA software (Becton Dickinson, San Jose, CA).

DISCUSSION

Flow cytometric analysis performed on the aspiratespecimen revealed a blastic neoplasm with the followingphenotype: dim CD45 positive, CD34 negative, CD117negative, CD4 positive, CD7 positive, CD56 positive,CD123 positive, TdT negative, MPO negative, CD3 nega-tive (surface and cytoplasmic), CD19 negative, CD20negative, 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 residualmaturing hematopoietic elements (Fig. 1). Sheets ofimmature-appearing mononuclear cells were noted onmarrow biopsy, and paraffin section immunohistochemi-cal studies confirmed that the blasts were MPO nega-tive, CD79a negative, CD3 negative, and stronglypositive for CD123, CD4, and CD56. A butyrate esterasecytochemical stain performed on the aspirate smear didnot provide evidence of monocytic differentiation. Theoverall features were considered diagnostic of blasticplasmacytoid dendritic cell neoplasm (BPDCN). Theskin lesions were also biopsied and showed involvementby BPDCN.

Additional Supporting Information may be found in the onlineversion of this article.

*Correspondence to: Dr. Christine G. Roth, Division of Hematopa-thology Department of Pathology, 200 Lothrop Street-Suite G300,Pittsburgh, PA 15213, USA.

E-mail: garciac@upmc.eduPublished online in Wiley Online Library (wileyonlinelibrary.com).

DOI: 10.1002/cyto.b.21060

Brief Communication

VC 2012 International Clinical Cytometry Society

Cytometry Part B (Clinical Cytometry) 00B:000–000 (2012)

BPDCN is the leukemic counterpart of plasmacytoiddendritic cells (PDC) (1). BPDCN is typically a disease ofelderly patients, although a few pediatric cases havebeen reported (2–4). A subset of patients have a pre-

existing myeloid neoplasm such as myelodysplasia, simi-lar to this case (4). Cutaneous lesions are often presentat the time of diagnosis, and isolated skin lesions may bethe initial presenting feature. However, BPDCN widelydisseminates, and despite an initial response to systemicchemotherapy, relapses are frequent in the absence ofallogeneic hematopoietic stem cell transplantation(allo-SCT). Treatment with acute myeloid leukemia(AML)-type induction chemotherapy regimens followedby allo-SCT at the first complete remission has beenadvocated (4,5). Although the older age of the patientpopulations presents a challenge to the treating hematol-ogist/oncologist, reduced-intensity conditioning allo-SCThas been shown to be effective in patients up to 70years of age (6).

However, the disease must first be correctly classifiedin order to enable appropriate therapy. Although BPDCNis a newly defined entity in the 2008 WHO classification,it is not a new disease, and previously had been knownas ‘‘CD4þ/CD56þ hematodermic neoplasm’’ as well as‘‘blastic NK-cell lymphoma’’ (4,7–9). Given that the neo-plastic cells lack lineage-specific myeloid, B, or T-cellantigens, extensive immunophenotypic characterizationmust be employed to establish the diagnosis. The emer-gence of more specific PDC markers such as CD123 has

FIG. 2. Flow cytometric histograms detailing antigenic expression pattern of the dim CD45 positive blastic population (colored pink).

FIG. 1. Wright-Giemsa-stained bone marrow aspirate smear demon-strating numerous blasts. Note the cytoplasmic ‘‘tails’’ (500�).

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made it possible to identify the PDC origin of BPDCN(10).

The primary differential diagnosis is with other typesof precursor myeloid or lymphoid neoplasms, and famili-arity with the immunophenotypic spectrum of BPDCN isessential. The neoplastic cells are typically dim CD45positive and may be TdT positive, compatible with blas-tic, immature cells (4,10,11). Although TdT expression ismore commonly seen in precursor lymphoid neoplasms,in contrast to lymphoblastic leukemias, BPDCN will notexhibit lineage-specific markers such as CD3, CD19,CD79a, or cytoplasmic CD22, although expression of theT-cell associated antigens CD2 and CD7 has beenreported (2). Lack of CD3 and expression of CD56 maybe seen in natural killer (NK) cell neoplasms; however,CD8 rather than CD4 is characteristic of NK cell neo-plasms, which also typically have expression of the epsi-lon chain of CD3. Although BPDCN may showexpression of the myeloid-associated antigen CD33, thelineage-specific marker myeloperoxidase (MPO) is nega-tive, CD34 is not expressed, and CD117 positivity hasonly rarely been reported, in contrast to many AML(2,3). The CD4þ/CD56þ phenotype characteristic ofBPDCN may overlap with monocytic AML, which canlack expression of CD34, CD117, and MPO (12). In addi-

tion, CD36 and CD68 expression may be seen in bothBPDCN as well as monocytic AML. In difficult cases,cytochemical staining may be a useful diagnostic adjunct,as monocytic AML should exhibit positivity for non-spe-cific esterase (NSE) whereas BPDCN is NSE negative.Given that a subset of BPDCN will lack expression ofCD4 and/or CD56, utilizing PDC-specific markers is rec-ommended in order to establish the diagnosis. CD123 isa robust PDC marker which has been extensively studiedin prior flow cytometric studies, however, may also beseen in other hematologic malignancies such as AML,lymphoblastic leukemias, and hairy cell leukemias(13,14). Additional immunohistochemical antibodies foruse in tissue sections have become available to helpidentify PDC origin, including TCL1, BDCA-2, andCD2AP (10,15,16). These studies may be useful to corre-late with the results of the flow cytometric analysis.

In summary, this case is an example of BPDCN, a rarebut distinctive neoplasm with an aggressive clinicalcourse. Familiarity with the immunophenotype (CD4þ,CD56þ, CD123þ, occasionally TdTþ, lack of lineagespecific markers) enables distinction from other hemato-poietic neoplasms with immunophenotypic overlap,which is essential for establishing the diagnosis andensuring appropriate therapy.

FIG. 3. Flow cytometric histograms detailing antigenic expression pattern of the blastic population (colored red) as identified by light scattercharacteristics.

BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM 3

Cytometry Part B: Clinical Cytometry

CASE 5 DIAGNOSIS: Blastic PlasmacytoidDendritic Cell Neoplasm

LITERATURE CITED

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2. Jacob MC, Chaperot L, Mossuz P, Feuillard J, Valensi F, Leroux D,Bene MC, Bensa JC, Briere F, Plumas J. CD4þ CD56þ lineage nega-tive malignancies: A new entity developed from malignant earlyplasmacytoid dendritic cells. Haematologica 2003;88:941–955.

3. Jegalian AG, Buxbaum NP, Facchetti F, Feuillard J, Valensi F, LerouxD, Bene MC, Bensa JC, Briere F, Plumas J. Blastic plasmacytoid den-dritic cell neoplasm in children: Diagnostic features and clinicalimplications. Haematologica 2010;95:1873–1879.

4. Feuillard J, Jacob MC, Valensi F, Maynadie M, Gressin R, Chaperot L,Arnoulet C, Brignole-Baudouin F, Drenou B, Duchayne E, et al. Clini-cal and biologic features of CD4(þ)CD56(þ) malignancies. Blood2002;99:1556–1563.

5. Male HJ, Davis MB, McGuirk JP, Abhyankar S, Aljitawi OS, Zhang D,Ganguly S. Blastic plasmacytoid dendritic cell neoplasm should betreated with acute leukemia type induction chemotherapy andallogeneic stem cell transplantation in first remission. Int J Hematol2010;92:398–400.

6. Dietrich S, Andrulis M, Hegenbart U, Schmitt T, Bellos F, MartensUM, Meissner J, Kramer A, Ho AD, Dreger P. Blastic plasmacytoiddendritic cell neoplasia (BPDC) in elderly patients: Results of atreatment algorithm employing allogeneic stem cell transplantationwith moderately reduced conditioning intensity. Biol Blood MarrowTransplant 2011;17:1250–1254.

7. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H,Thiele J, Vardiman JW, editors. WHO Classification of Tumours ofHaematopoietic and Lymphoid Tissues, 4th ed. Lyon, France: IARCPress; 2008.

8. Weaver J, Hsi ED. CD4þ/CD56þ hematodermic neoplasm (blasticNK-cell lymphoma). J Cutan Pathol 2008;35:975–977.

9. Herling M, Jones D. CD4þ/CD56þ hematodermic tumor: The fea-tures of an evolving entity and its relationship to dendritic cells.Am J Clin Pathol 2007;127:687–700.

10. Marafioti T, Paterson JC, Ballabio E, Reichard KK, Tedoldi S, Hollo-wood K, Dictor M, Hansmann ML, Pileri SA, Dyer MJ, et al. Novelmarkers of normal and neoplastic human plasmacytoid dendriticcells. Blood 2008; 111:3778–3792.

11. Reichard KK, Burks EJ, Foucar MK, Wilson CS, Viswanatha DS, Hoz-ier JC, Larson RS. CD4(þ) CD56(þ) lineage-negative malignanciesare rare tumors of plasmacytoid dendritic cells. Am J Surg Pathol2005;29:1274–1283.

12. Xu Y, McKenna RW, Wilson KS, Karandikar NJ, Schultz RA, KroftSH. Immunophenotypic identification of acute myeloid leukemiawith monocytic differentiation. Leukemia 2006;20:1321–1324.

13. Rollins-Raval MA, Roth CG. The value of immunohistochemistry forCD14, CD123, CD33, myeloperoxidase and CD68R in the diagnosisof acute and chronic myelomonocytic leukaemias. Histopathology2012;60:933–942.

14. Munoz L, Nomdedeu JF, Lopez O, Carnicer MJ, Bellido M, AventinA, Brunet S, Sierra J. Interleukin-3 receptor alpha chain (CD123) iswidely expressed in hematologic malignancies. Haematologica2001;86:1261–1269.

15. Herling M, Teitell MA, Shen RR, Medeiros LJ, Jones D. TCL1expression in plasmacytoid dendritic cells (DC2s) and the relatedCD4þ CD56þ blastic tumors of skin. Blood 2003;101: 5007–5009.

16. Pilichowska ME, Fleming MD, Pinkus JL, Pinkus GS. CD4þ/CD56þhematodermic neoplasm (‘‘blastic natural killer cell lymphoma’’):Neoplastic cells express the immature dendritic cell marker BDCA-2and produce interferon. Am J Clin Pathol 2007;128:445–453.

Table 1Antibody and fluorochrome combinations utilized

Tube FITC PE

PerCP-

Cy5.5 APC PE-Cy7 APC-H7 V450 V500

1 CD14 CD13/33 CD45 CD34

2 CD15 CD33 CD117 HLA-DR

3 CD16/57 CD7 CD4 CD56 CD3 CD8 CD2 CD45

4 CD16 CD13 CD45 CD11b

5 CD36 CD64 CD45 CD34

6 CD38 CD22 CD20 CD10

7 CD7 CD123 CD45 CD56

8 Kappa Lambda CD19 CD5

9 cTdt cMPO cCD3 cCD34

c: cytoplasmic.

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