blastic plasmacytoid dendritic cell neoplasm: a clinicopathologic review

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Resident Short Review Blastic Plasmacytoid Dendritic Cell Neoplasm A Clinicopathologic Review Yang Shi, MD, PhD; Endi Wang, MD, PhD Blastic plasmacytoid dendritic cell neoplasm is a rare entity grouped with the acute myeloid leukemia–related precursor neoplasms in the 2008 World Health Organiza- tion classification. It was previously postulated to originate from natural killer cells, T cells, or monocytes but is now believed to arise from the plasmacytoid dendritic cell. The pathogenesis of blastic plasmacytoid dendritic cell neo- plasm is not well understood, although the neoplasm demonstrates frequent deletion of tumor suppressor genes, including RB1, CDKN1B, CDKN2A, and TP53. Blastic plasmacytoid dendritic cell neoplasm is a clinically aggressive tumor that often initially presents as cutaneous lesions and subsequently progresses to bone marrow involvement and leukemic dissemination. It is character- ized by enhanced expression of CD56, CD4, and CD123, which can be detected by flow cytometry/immunohisto- chemistry. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and some mature T-cell lymphomas/leukemias. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplant may improve survival. (Arch Pathol Lab Med. 2014;138:564–569; doi: 10.5858/ arpa.2013-0101-RS) B lastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematopoietic malignancy derived from the precursors of plasmacytoid dendritic cells. This neo- plasm is rare and has only recently been recognized as a distinct neoplastic entity. 1 In the past, it was referred to by several names, including blastic NK-cell lymphoma, agranular CD4 þ natural killer cell leukemia, and agranular CD4 þ CD56 þ hematodermic neoplasm, among others. The several syno- nyms and periodic name changes reflect the uncertainty of the cell origin and the challenges involved in classifying this hematopoietic neoplasm. Although the terminology may evolve further, this neoplasm is currently designated BPDCN because of its close resemblance, both in immu- nophenotype and gene expression profile, to the precursor of the plasmacytoid dendritic cell. Currently, BPDCN is categorized under ‘‘acute myeloid leukemia (AML) and related precursor neoplasms’’ in the 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2 CLINICAL FEATURES Blastic plasmacytoid dendritic cell neoplasms usually occur in elderly patients, with a mean age between 60 and 70 years; however, they can present at any age, even in children. 1,3,4 It more often occurs in men (male to female ratio, 3:1) but has no known racial or ethnic predilection. The tumor is characterized by a high frequency of cutaneous lesions at diagnosis, accompanied by extracutaneous in- volvement of the bone marrow, peripheral blood, and lymph nodes. 5 Patients typically present with asymptomatic, solitary or multiple skin lesions, such as nodules, plaques, or bruiselike lesions that can range in size from a few millimeters to 10 cm. The skin lesions can be associated with erythema, hyperpigmentation, purpura, or ulceration. Extracutaneous disease is present in most patients at diagnosis, often involving the regional lymph nodes. As the disease continues to progress, the peripheral blood and bone marrow become involved. In the Ann Arbor staging system, 6 most patients (66%) at diagnosis have stage IV disease, whereas a few patients (24%) are classified as stage I. It is extremely rare for BPDCN patients to present without cutaneous involvement, but even then, most of the patients will develop cutaneous lesions after an initial extracutaneous presentation. 6 At diagnosis, mild to moderate peripheral cytopenias are common, but overt systemic symptoms are rare. As the disease progresses, patients develop fulminant leukemia, particularly in the terminal stage of the disease, regardless of whether the patient presents with or without cutaneous lesions. In 10% to 20% of patients with BPDCN, coincident myelodysplasia is identified that can subsequent- ly lead to the development of acute myelomonocytic leukemia or AML. 7 HISTOLOGY In cutaneous lesions, BPDCN typically infiltrates the dermis but spares the epidermis. As the disease progresses, it frequently extends into the subcutaneous fat. The neoplastic cells tend to aggregate in the superficial to mid dermis in a perivascular and/or periadnexal distribution; although, less frequently, they may be seen as a lichenoid Accepted for publication June 13, 2013. From the Department of Pathology, Duke University Medical Center, Durham, North Carolina. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Yang Shi, MD, PhD, Department of Pathology, Duke University Medical Center 3712, Durham, NC 27710 (e-mail: yang. [email protected]). 564 Arch Pathol Lab Med—Vol 138, April 2014 Blastic Plasmacytoid Dendritic Cell Neoplasm—Shi & Wang

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Resident Short Review

Blastic Plasmacytoid Dendritic Cell Neoplasm

A Clinicopathologic Review

Yang Shi, MD, PhD; Endi Wang, MD, PhD

� Blastic plasmacytoid dendritic cell neoplasm is a rareentity grouped with the acute myeloid leukemia–relatedprecursor neoplasms in the 2008 World Health Organiza-tion classification. It was previously postulated to originatefrom natural killer cells, T cells, or monocytes but is nowbelieved to arise from the plasmacytoid dendritic cell. Thepathogenesis of blastic plasmacytoid dendritic cell neo-plasm is not well understood, although the neoplasmdemonstrates frequent deletion of tumor suppressor genes,including RB1, CDKN1B, CDKN2A, and TP53. Blasticplasmacytoid dendritic cell neoplasm is a clinicallyaggressive tumor that often initially presents as cutaneouslesions and subsequently progresses to bone marrowinvolvement and leukemic dissemination. It is character-ized by enhanced expression of CD56, CD4, and CD123,which can be detected by flow cytometry/immunohisto-chemistry. The differential diagnoses include myeloidsarcoma/acute myeloid leukemia, T-cell lymphoblasticleukemia/lymphoma, NK-cell lymphoma/leukemia, andsome mature T-cell lymphomas/leukemias. Patients usuallyrespond to initial chemotherapy but often relapse. Stemcell transplant may improve survival.

(Arch Pathol Lab Med. 2014;138:564–569; doi: 10.5858/arpa.2013-0101-RS)

B lastic plasmacytoid dendritic cell neoplasm (BPDCN) isan aggressive hematopoietic malignancy derived from

the precursors of plasmacytoid dendritic cells. This neo-plasm is rare and has only recently been recognized as adistinct neoplastic entity.1 In the past, it was referred to byseveral names, including blastic NK-cell lymphoma, agranularCD4þ natural killer cell leukemia, and agranular CD4þCD56þ

hematodermic neoplasm, among others. The several syno-nyms and periodic name changes reflect the uncertainty ofthe cell origin and the challenges involved in classifying thishematopoietic neoplasm. Although the terminology mayevolve further, this neoplasm is currently designatedBPDCN because of its close resemblance, both in immu-

nophenotype and gene expression profile, to the precursorof the plasmacytoid dendritic cell. Currently, BPDCN iscategorized under ‘‘acute myeloid leukemia (AML) andrelated precursor neoplasms’’ in the 2008 World HealthOrganization Classification of Tumours of Haematopoietic andLymphoid Tissues.2

CLINICAL FEATURES

Blastic plasmacytoid dendritic cell neoplasms usuallyoccur in elderly patients, with a mean age between 60 and70 years; however, they can present at any age, even inchildren.1,3,4 It more often occurs in men (male to femaleratio, 3:1) but has no known racial or ethnic predilection.The tumor is characterized by a high frequency of cutaneouslesions at diagnosis, accompanied by extracutaneous in-volvement of the bone marrow, peripheral blood, andlymph nodes.5 Patients typically present with asymptomatic,solitary or multiple skin lesions, such as nodules, plaques, orbruiselike lesions that can range in size from a fewmillimeters to 10 cm. The skin lesions can be associatedwith erythema, hyperpigmentation, purpura, or ulceration.Extracutaneous disease is present in most patients atdiagnosis, often involving the regional lymph nodes. Asthe disease continues to progress, the peripheral blood andbone marrow become involved. In the Ann Arbor stagingsystem,6 most patients (66%) at diagnosis have stage IVdisease, whereas a few patients (24%) are classified as stageI. It is extremely rare for BPDCN patients to present withoutcutaneous involvement, but even then, most of the patientswill develop cutaneous lesions after an initial extracutaneouspresentation.6 At diagnosis, mild to moderate peripheralcytopenias are common, but overt systemic symptoms arerare. As the disease progresses, patients develop fulminantleukemia, particularly in the terminal stage of the disease,regardless of whether the patient presents with or withoutcutaneous lesions. In 10% to 20% of patients with BPDCN,coincident myelodysplasia is identified that can subsequent-ly lead to the development of acute myelomonocyticleukemia or AML.7

HISTOLOGY

In cutaneous lesions, BPDCN typically infiltrates thedermis but spares the epidermis. As the disease progresses,it frequently extends into the subcutaneous fat. Theneoplastic cells tend to aggregate in the superficial to middermis in a perivascular and/or periadnexal distribution;although, less frequently, they may be seen as a lichenoid

Accepted for publication June 13, 2013.From the Department of Pathology, Duke University Medical

Center, Durham, North Carolina.The authors have no relevant financial interest in the products or

companies described in this article.Reprints: Yang Shi, MD, PhD, Department of Pathology, Duke

University Medical Center 3712, Durham, NC 27710 (e-mail: [email protected]).

564 Arch Pathol Lab Med—Vol 138, April 2014 Blastic Plasmacytoid Dendritic Cell Neoplasm—Shi & Wang

infiltrate in the superficial dermis (Figure 1, A). At highmagnification, BPDCN is characterized by a monotonouspopulation of small to medium cells with irregular nuclearcontours, fine to evenly dispersed chromatin, 1 to 3 smallnucleoli, and scant to moderate amounts of cytoplasm(Figure 1, B).

Lymph nodes can be partially involved, particularly in aninterfollicular distribution, or BPDCN can show diffuseinvolvement of the lymph nodes and complete effacementof lymph node architecture. Bone marrow involvement isfocal at initial diagnosis, with small clusters or an interstitialinfiltration of tumor cells, but extensive bone marrowreplacement can be noted, particularly at the advancedstage. The neoplastic cells can be present in the peripheralblood and resemble circulating leukemic lymphoid ormyeloid blasts (Figure 1, C), especially when the bonemarrow is extensively involved (Figure 1, D and E). Theneoplastic cells in the bone marrow aspirate tests may showtypical pearl-necklacelike, submembranous, cytoplasmicvacuoles and elongated, agranular cytoplasm (Figure 1, D).In cases with extensive bone marrow involvement, thebiopsy section is usually hypercellular with a brisk infiltrateof neoplastic cells and a marked decrease in the normalhematopoietic elements (Figure 1, E). Of note, the residualhematopoietic elements, including megakaryocytes, granu-locytes, and erythroid precursors, may show some dysplasticchanges both in the bone marrow and in the peripheralblood (Figure 1, C).

ANCILLARY STUDIES

By immunohistochemistry, the BPDCN cells typicallyexpress CD56 (Figure 2, A), CD4 (Figure 2, B), CD123(Figure 2, C), and T-cell leukemia/lymphoma 1 (TCL1). Theycan also express other plasmacytoid dendritic cell–associat-ed antigens, such as blood dendritic cell antigen 2 (BDCA-2)/CD303 and the interferon a–dependent moleculeMxA.8–10 Cutaneous lymphocyte associated antigen (CLA)is usually highly expressed in skin lesions.11 Of note,staining of CD123 is typically strong, whereas CD4 andCD56 can be weak in some cases. In rare cases, theneoplastic cells do not express CD56, which raises aquestion of the diagnosis but does not exclude thepossibility if the other characteristic features are present.CD43 is expressed in more than 95% of cases (Figure 2, D).12

The neoplastic cells are usually negative for lineage-specificantigens of T cells, B cells, granulocytes, and monocytes. Forinstance, results are regularly negative for CD3, CD5,cytotoxic molecules (granzyme B1, TIA1, and perforin),CD20, CD79a, PAX5, myeloperoxidase (MPO), CD117, andlysozyme. However, a few myeloid-associated antigens havebeen seen in a significant number of cases. In particular,CD68, an antigen typically expressed by granulocytes andhistiocytes as well as normal plasmacytoid dendritic cells, isnoted in 50% of cases. CD33, a myeloid antigen, isfrequently found in the neoplastic cells of BPDCN. Inaddition, a few T-cell–associated antigens have beenidentified frequently, including CD2, CD7, CD43, andCD45RA. Interestingly, terminal deoxynucleotide transfer-ase (TdT), a landmark antigen for precursor lymphoid cells,is found in one-third to one-half of cases. Two otherhematopoietic precursor–associated antigens, CD38 andHLA-DR, are expressed in most cases. However, CD10and CD34 are typically not expressed. Epstein-Barr virus(EBV)–specific antigens by immunohistochemistry and

EBV–encoded small nuclear RNA by in situ hybridizationare universally negative.

Flow cytometric analysis is particularly valuable inestablishing the diagnosis of BPDCN, especially in caseswith extensive bone marrow involvement and circulatingneoplastic cells. As seen in immunohistochemistry, flowcytometric analysis can detect neoplastic cells of BPDCNwith CD56, CD123, and CD4 (Figure 2, E through H). Theadvantage of flow cytometry in the diagnosis of BPCDN isboth quantitative and qualitative. Flow cytometry not onlydemonstrates antigen coexpression but also shows thedensity of each antigen quantitatively. For instance, theexpression of CD123 can be seen on hematopoieticprecursors, many mature or maturing myeloid and lym-phoid cells, and also their neoplastic counterparts. Usually,however, the antigen density on those cells is relatively low,and, therefore, the staining of CD123 by flow cytometry isdim to moderate. In contrast, CD123 expression in BPDCNis usually higher and more homogeneous. The brighterCD123 coupled with the coexpression of CD56 and CD4 isalmost pathognomonic of this disease in flow cytometricanalysis (Figure 2, E through H). Although BPDCNs showdim to moderate expression of CD45, a significant fractiondemonstrates no expression of leukocyte common antigen,and the neoplastic population falls into the ‘‘blast gate’’ onCD45 versus side scatter plot (Figure 2, E). In addition toimmunophenotypic features noted above in immunohisto-chemistry, the neoplastic cells are typically negative forsurface CD3, surface T-cell receptor (TCR), CD19, CD22,and CD13 by flow cytometric analysis. A limitation of flowcytometry is detection of BPDCN in the early stages of thedisease. Initially, BPDCN typically presents with skinmanifestations. Sufficient, viable, single-cell suspensionscan not be reliably prepared from a routine skin-punchbiopsy. In such a situation, immunohistochemistry is themain ancillary study for diagnosis of BPDCN.

Karyotypic analysis frequently shows complex aberrationssimilar to those seen in myelodysplastic syndromes or AMLarising from myelodysplastic syndromes. Cytogenetic stud-ies have shown a predominance of genomic losses, affecting5q21 or 5q34 (72%), 12p13 (64%), 13q13–q21 (64%), 6q23–qter (50%), 15q (43%), and the entire chromosome 9(28%).13 Array-based comparative genomic hybridizationdemonstrates that complete or partial chromosomal losseslargely outnumber the gains, with deleted regions com-monly involving 9p21.3 (cyclin-dependent kinase inhibitor2A/2B, CDKN2A/CDKN2B), 13q13.1–q14.3 (retinoblastomaprotein 1, RB1), 12p13.2–p13.1 (CDKN1B), 13q11–q12(serine/threonine-protein kinase LATS2), and 7p12.2 (Ikarosfamily zinc finger protein 1, IKZF1). The CDKN2A/CDKN2Bdeletion has been confirmed by fluorescence in situhybridization. Statistical analysis of the overall survival in21 cases of BPDCN showed an association of poor outcomewith biallelic loss of locus 9p21.3.14 In contrast to B-cell or T-cell neoplasms, gene rearrangement analysis typicallydetects no clonal rearrangements of immunoglobulin heavychain, j light chain, or TCR gene.

HISTOGENESIS AND PATHOGENESIS

Blastic plasmacytoid dendritic cell neoplasm is thought tobe derived from precursors of the plasmacytoid dendriticcells (PDCs) because of its resemblance to the normalcounterpart in immunophenotype, expression profile, andbiologic function.15 The PDCs are naturally found in the

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Figure 1. Morphologic features of blastic plasmacytoid dendritic cell neoplasm. A, A low magnification of a skin-punch biopsy shows a denseneoplastic infiltrate in the superficial dermis with patchy extension into the mid and deep dermis as well as the subcutaneous tissue. A Grenz zonebetween the dermal infiltrate and spared epidermis is present. Perivascular distribution of the neoplastic infiltrate in the mid dermis is also seen. B,High-power magnification of the deep dermal/subcutaneous infiltrate exhibits a monotonous population of medium-sized blastic cells with irregularnuclear contours, dispersed chromatin, and scant to moderate cytoplasm. C, Peripheral blood smear shows 3 blastic or abnormal mononuclear cellswith relatively high nuclear to cytoplasmic ratio, oval to indented nuclear contours, slightly dispersed chromatin, somewhat prominent nucleolus, andscant to moderate amounts of agranular cytoplasm; a unilobed neutrophil with clumped chromatin suggestive of the pseudo–Pelger-Huett anomaly isnoted in lower, right corner. D, Bone marrow aspirate test demonstrates increases in neoplastic cells in a background of hematopoiesis. Mostneoplastic cells exhibit elongated agranular cytoplasm. E, Section of the bone marrow biopsy shows an interstitial infiltrate or neoplastic proliferation

566 Arch Pathol Lab Med—Vol 138, April 2014 Blastic Plasmacytoid Dendritic Cell Neoplasm—Shi & Wang

bone marrow, peripheral blood, umbilical cord blood, andthe T zone in human lymphoid tissues. In the peripheralblood, they account for less than 0.1% of circulating whiteblood cells. Similar to BPDCN cells, PDCs have eccentricnuclei and express high levels of CD4, CD123, and HLA-DR, in addition to low levels of CD43 and CD68. They alsoexpress CD303 (blood dendritic cell antigen 2, BDCA2),cutaneous lymphocyte-associated antigen (CLA), granzymeB, and TCL1. Plasmacytoid dendritic cells do not expressCD34 or CD11c, similar to their presumed neoplasticcounterpart, the blastic plasmacytoid dendritic cells.

The main characteristics of PDCs are high-level expres-sion of CD123, which is an interleukin-3 a-chain receptor.Plasmacytoid dendritic cells serve as a principal source ofinterferon a. They accumulate in inflammatory sites andcontribute to the inflammatory and immune response.Plasmacytoid dendritic cells are increased in a variety ofinflammatory conditions, including granulomatous lymph-

adenitis, Kikuchi-Fujimoto lymphadenopathy, hyaline-vas-cular Castleman disease, Hodgkin lymphoma, and allergicrhinitis. They can also be seen in the skin of patients withpsoriasis, lupus erythematosus, and hydroa vaccini-forme.16,17 It remains to be further investigated whetherany of these inflammatory conditions is a precursor lesion ofBPDCN.

Because of similarities in their immunophenotypes andcell morphologies, PDCs have previously been referred to asplasmacytoid T cells or plasmacytoid monocytes. Becauseexpression of both lymphoid and myeloid markers is foundon PDCs, the lineage assignment is still being debated.Because myelodysplasia and AML can occur during thecourse of BPDCN, there is a strong argument that PDCsmay belong to the myelomonocytic lineage. Therefore,BPDCN is currently grouped with the category of AML andrelated precursor neoplasms in the 2008 World HealthOrganization Classification of Tumours of Haematopoietic and

Figure 2. Immunohistochemical studies and flow cytometric analysis of blastic plasmacytoid dendritic cell neoplasm. A through D, The neoplasticcells are positive for CD56 (A), CD4 (B), CD123 (C), and CD43 (D). E through H, Flow cytometric analysis of bone marrow aspirate sample. Theabnormal cell population is designated with a light blue color. It is negative or extremely dim for CD45 (E), positive for bright CD123 (F), CD56 (F),moderate CD4 (G), but it is negative for CD14 (G), CD117 (H), and CD34 (H) (original magnifications 3400 [A through D]).

with markedly diminished trilineage hematopoiesis. The inset shows small to medium lymphoid cells (hematoxylin-eosin, original magnifications 320[A], 3400 [B and inset], and 3200 [E]; Wright-Giemsa, original magnification 31000 [C and D]).

Arch Pathol Lab Med—Vol 138, April 2014 Blastic Plasmacytoid Dendritic Cell Neoplasm—Shi & Wang 567

Lymphoid Tissue.2 Blastic plasmacytoid dendritic cell neo-plasm cells demonstrate a recurrent combination ofdeletions in several tumor suppressor genes, includingRB1, CDKN1B, CDKN2A, and tumor protein p53 (TP53).The TET2 gene (Ten–eleven translocation–2), located onband 4q24, has been shown to be mutated in BPDCN,myelodysplastic syndromes, chronic myelomonocytic leu-kemia, and AML, which provides additional evidence thatBPDCN is a myeloid related neoplasm.18 Disruption of cellcycle at the G1/S transition is thought to represent a biologichallmark of BPDCN and possibly contributes to itspathogenesis.14

DIFFERENTIAL DIAGNOSES

The diagnosis of BPDCN is based on clinical features,morphologic findings, immunophenotypic profile, andcytogenetic and molecular data. Among these, immuno-phenotyping of neoplastic cells plays an important role inthe diagnosis of the disease. Because of the overlap of theimmunophenotypic features with other hematopoieticneoplasms, extensive immunophenotypic analysis is neededfor a definitive diagnosis. In particular, myeloid sarcoma/AML, T-cell lymphoblastic leukemia/lymphoma (T-ALL/LBL), NK-cell lymphoma/leukemia, and some mature T-celllymphomas/leukemias should be excluded before establish-ing a diagnosis of BPDCN.

The early skin presentation of BPDCN needs to bedistinguished from cutaneous myeloid sarcoma because ofits frequent expression of myeloid antigens, including CD68,CD33, and CD43. However, staining results are negative formyeloperoxidase, which is a more-specific antigen formyeloid lineage and is often positive in most cutaneousmyeloid sarcomas. In addition, CD68 staining in BPDCN istypically cytoplasmic and dotlike, whereas cutaneousmyeloid sarcoma shows diffuse cytoplasmic staining.Moreover, in cutaneous myeloid sarcoma, associated matureor maturing granulocytes are often noted on close inspec-tion. Conversely, a significant proportion of cutaneousmyeloid sarcoma exhibits myelomonocytic or monoblasticdifferentiation and may thus express CD4, CD56, and/orCD123. Although the expression of those antigens mimicsthat of BPDCN, the expression of CD123 in cutaneousmyeloid sarcoma is usually much weaker than that ofBPDCN. Additionally, myeloid sarcoma tends to expressCD117, CD34, and/or lysozyme, which are usually negativein BPDCN. Moreover, TCL1 is positive in 90% of BPDCNsbut in only 17% of AMLs.11 The distinction of BPDCN fromAML is more challenging when BPDCN extensivelyinvolves bone marrow, especially in the cases withsignificant circulating neoplastic cells. These cases closelyresemble acute leukemia because of their blastic morphol-ogy and leukemia-type infiltration in bone marrow.Fortunately, flow cytometric immunophenotyping is rou-tinely performed in most clinical laboratories in Westerncountries, and a definitive diagnosis can be established afteran extensive immunophenotypic analysis.

Because of expression of CD4 and other T-cell antigens, aswell as reactivity to TdT in a many cases, cutaneous T-ALL/LBL or late-stage leukemic dissemination needs to beexcluded. Usually, T-ALL/LBL is positive for T-cell–specificantigens, including cytoplasmic CD3, CD5, CD2, and CD7,in addition to TdT. Although the CD4 subset restriction canbe seen in rare cases of T-ALL/LBL, most are either doublenegative or double positive for CD4 and CD8. Therefore, a

case with CD4 expression but no other T-cell lineage–specific antigens should always raise the possibility ofBPDCN, unless all clinical findings, pathologic features, andgenetic tests are fulfilled. Usually, T-ALL/LBL has a clonalrearrangement of the TCR gene detected by polymerasechain reaction, whereas BPDCN is negative for the test.

Blastic plasmacytoid dendritic cell neoplasm should bedifferentiated from extranodal NK/T-cell lymphoma, nasaltype. The skin is the most common extranasal site forextranodal NK/T-cell lymphoma, nasal type. This distinc-tion may present a particular challenge because extra-nodal NK/T-cell lymphoma, like BPDCN, can express T-cell antigens, as well as CD56. Extranodal NK/T-celllymphoma typically exhibits an angiocentric and angio-destructive growth pattern and demonstrates expressionof cytoplasmic CD3 (e chain) as well as cytotoxicmolecules, whereas BPDCN does not. Importantly, extra-nodal NK/T-cell lymphoma is an EBV-driven lymphoidneoplasm, so it should be positive for EBV studies, oftenwith type II latency (latent membrane protein 1 positiveand EBV nuclear antigen 2 negative).

The BPDCN can sometimes be confused with cutaneousperipheral T-cell lymphoma or cutaneous involvement by T-cell lymphoma, especially in some cases that show loss ofpan–T-cell antigens and express CD56. However, by usingan extensive immunohistochemical panel, that distinction ispossible. In addition, the TCR gene rearrangement study isoften positive for clonal rearrangement in T-cell lymphomaand is characteristically negative in BPDCN.

TREATMENT AND CLINICAL OUTCOMEOF THE DISEASE

The clinical course of BPDCN is aggressive, with a mediansurvival of 12 to 14 months, irrespective of the initialpresentation of the disease. Advanced age and advancedclinical stage are both poor prognostic indicators. Because ofits low incidence, there is no consensus on optimal therapyfor BPDCN. Most patients are treated with multiagentchemotherapy, such as CHOP (cyclophosphamide, doxoru-bicin, vincristine, and prednisone), or hyper-CVAD (com-bination of course A: cyclophosphamide, vincristine,doxorubicin; and course B: methotrexate and cytarabine, inan alternating fashion). Patients usually respond well toinitial chemotherapy, with complete response rates of 47%to 86%. However, the disease often relapses, and therelapsed disease is typically resistant to the previously usedchemotherapeutic agents. More recent clinical studiesdemonstrated that high-dose chemotherapy followed byallogeneic stem cell transplant from matched related orunrelated donors could provide a durable remission, even inelderly patients.19 In contrast to adult cases, BPDCNs inchildren are clinically less aggressive. Treatment withprotocols for high-risk acute lymphoblastic leukemia seemsto be effective. Stem cell transplantation in the pediatricpopulation is reserved for patients who relapse. Outcomesare more favorable in cases that lack cutaneous disease atpresentation, although a comparison of cutaneous andnoncutaneous cases might be confounded by differences intreatment regimens.20 Conversely, patients presenting withisolated cutaneous lesions survive longer. It needs to beverified whether genetic analysis, such as florescence in situhybridization for CDKN2A/CDKN2B, can be applied tostratify the cases into prognostic groups.14

568 Arch Pathol Lab Med—Vol 138, April 2014 Blastic Plasmacytoid Dendritic Cell Neoplasm—Shi & Wang

We thank Evan Kulbacki, MD, for editing the manuscript.

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15. Grouard G, Rissoan MC, Filgueira L, Durand I, Banchereau J, Liu YJ. Theenigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)-3and CD40-ligand. J Exp Med. 1997;185(6):1101–1111.

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