Blastic plasmacytoid dendritic cell neoplasm in the pediatric
population: diagnostic features and clinical implications
by Armin G. Jegalian, Nataliya P. Buxbaum, Fabio Facchetti, Mark Raffeld,
Stefania Pittaluga, Alan S. Wayne, and Elaine S. Jaffe
Haematologica 2010 [Epub ahead of print]
Citation: Jegalian AJ, Buxbaum NP, Facchetti F, Raffeld M, Pittaluga S, Wayne AS,
and Jaffe ES. Blastic plasmacytoid dendritic cell neoplasm in the pediatric population:
diagnostic features and clinical implications.
Haematologica. 2010; 95:xxx
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Published Ahead of Print on July 27, 2010, as doi:10.3324/haematol.2010.026179.
Blastic plasmacytoid dendritic cell neoplasm in the pediatric population: diagnostic
features and clinical implications
Armin G. Jegalian,1 Nataliya P. Buxbaum,2 Fabio Facchetti,3 Mark Raffeld,1
Stefania Pittaluga,1 Alan S. Wayne,2 and Elaine S. Jaffe1
1Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National
Institutes of Health, Bethesda, MD, USA; 2Pediatric Oncology Branch, Center for Cancer
Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;
and 3Department of Pathology, University of Brescia, Brescia, Italy
Dr. Jegalian is currently affiliated with the Department of Clinical Pathology at the
Cleveland Clinic, Cleveland, OH, USA
Elaine S. Jaffe, Hematopathology Section, Laboratory of Pathology, National Cancer
Institute, National Institutes of Health, 10 Center Dr MSC 1500, Building 10 Room
2B42, Bethesda, MD, USA 20892. Phone: international +301.4960183.
Fax: international +301.4022415. E-mail: email@example.com
Running head: Pediatric blastic PDC neoplasms
The authors would like to thank the following physicians for sharing with us their
patients’ clinical histories and specimens: Dr. Denize Azambuja, Rio de Janeiro, Brazil;
Dr. Salvatore Bertolone, Louisville, KY, USA; Dr. Robin Hanson, St. Louis, MO, USA;
Dr. Paul Jubinsky, New Haven, CT, USA; Dr. Frank Keller, Atlanta, GA, USA; Dr.
Dennis Kuo, Paterson, NJ, USA; Dr. Anne-Marie Langevin, Houston, TX, USA; Dr.
Elaine Morgan, Chicago, IL, USA; Dr. Anne Nepo, Albany, NY, USA; Dr. John Torrey
Sandlund, Memphis, TN, USA; and Dr. Michael Weintraub, Jerusalem, Israel.
This work was supported by the Intramural Research Program of the Center for Cancer
Research, National Cancer Institute, NIH.
The online version of this article has a supplementary appendix.
Background. Blastic plasmacytoid dendritic cell neoplasm is a rare malignancy that
typically follows a highly aggressive clinical course in adults, whereas the pediatric
experience with this disease is very limited.
Design and Methods. This retrospective study analyzes the pathologic and clinical
findings in 9 cases presenting in patients under the age of 18 years that were reviewed at
our institution. In addition, we identified 20 well-documented additional pediatric cases
in the literature.
Results. In the combined analysis, the overall survival rate among the 25 patients with
available follow-up, all having received chemotherapy, was 72% (follow-up ranging from
9 months to 13 years, with a median of 30 months). The event-free survival rate was
64%. Nine patients were alive 5 years after the original diagnosis, although only 3 of
them had undergone hematopoietic stem cell transplantation – 1 in first complete
remission and 2 in second remission. Of the 7 patients who lacked cutaneous disease at
presentation, 100% survived, including 5 with survival beyond 5 years, although only 2
had undergone stem cell transplantation. Among the 18 patients who presented with
cutaneous disease and had follow-up available, only 11 survived (61%). Detailed
immunophenotypic characterization and clinical features of all cases are presented.
Unexpectedly, 3 of 4 cases of blastic plasmacytoid dendritic cell neoplasms tested
showed focal positivity for S-100. S-100 was negative in 28 acute myeloid leukemia
cases evaluated for this marker.
Conclusions. In contrast to adult cases, where long-term survival depends on stem cell
transplatation in first complete remission, blastic plasmacytoid dendritic cell neoplasms
are clinically less aggressive in children. Treatment with high-risk acute lymphoblastic
leukemia-type chemotherapy appears to be effective, and stem cell transplantation may
be reserved for children who relapse and achieve a second remission. Outcomes were
more favorable in cases that lacked cutaneous disease at presentation, although
comparison of cutaneous and noncutaneous cases might be confounded by differences in
treatment regimens. Focal expression of S-100 may be seen in concert with other
markers of plasmacytoid dendritic cells.
Key words: blastic plasmacytoid dendritic cell neoplasm, CD4+/CD56+ hematodermic
neoplasm, pediatric, acute myeloid leukemia, acute lymphoblastic leukemia, stem cell
transplant, S-100, immunophenotyping, dendritic cells.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare subtype of
acute leukemia and was formerly known as blastic natural killer (NK)-cell lymphoma and
CD4+/CD56+ hematodermic neoplasm.(1-5) Once postulated to originate from NK-
lineage precursors, accumulating phenotypic, functional, and genetic evidence has
pointed to derivation from hematopoietic precursors with commitment to the
plasmacytoid dendritic cell (PDC) lineage.(6-11) While their role in antigen presentation
has been debated, PDCs serve as a principal source of type I interferons and have been
implicated in a wide variety of immune functions, including antiviral immunity, anti-
tumor immunity, and peripheral tolerance.(12-13) The precise developmental pathway of
PDCs is somewhat controversial, but current evidence favors derivation from a common
macrophage and dendritic cell precursor.(14-15)
Due to its rarity and only recent recognition as a distinct clinicopathologic entity, no
standardized therapeutic approach has been established for BPDCN. Reimer et al.
published the most comprehensive retrospective study to date on the treatment and
outcome of BPDCN, then called CD4+CD56+ malignancy, studying 91 previously
published cases as well as 6 additional patients.(16) The authors concluded that with a
median survival of only 13 months and generally poor prognosis, high-dose
chemotherapy/radiotherapy followed by allogeneic stem cell transplantation (SCT)
performed in first complete remission (CR) offered the highest curative potential.
However, only 4 children were included in that study, as BPDCN predominantly affects
older adults. A more recent study advocating the use of SCT for this disease included
only one pediatric case among a total of 47 patients.(17)
The pediatric experience with BPDCN is especially limited, with only a few case reports
and small collections of cases described in the literature.(1-2, 11, 18-31) Historical
review of cases is somewhat problematic since recently validated PDC markers were not
routinely tested in the past. Recently identified key markers include CD123, the
interleukin-3 receptor ! chain, which is strongly expressed in BPDCN and is amenable to
immunohistochemical detection on formalin-fixed tissue,(7-8) TCL1 (T-cell
leukemia/lymphoma 1),(32-33) CD303/BDCA-2 (blood dendritic cell antigen-2),(28, 34)
and CD2AP (CD2-associated protein).(10) As CD56 expression may be nonspecific, the
former diagnostic category of blastic NK-cell lymphoma also encompassed cases of true
precursor NK-cell malignancy and primitive hematopoietic malignancies of other
lineages, such as acute monocytic leukemia, diseases that might behave differently.
We now report 9 cases of pediatric BPDCN, the largest such series described to date.
Older cases were re-evaluated with CD123, CD303/BDCA-2, TCL1, and CD2AP
immunohistochemistry for confirmation of the diagnosis. A comprehensive and critical
literature search identified 20 additional cases of BPDCN presenting in children. The
objectives of this study were to determine optimal therapy for this exceedingly rare
disease based on the cumulative clinical data that is available, and also to compare cases
with the typical cutaneous presentation to leukemic variants lacking cutaneous
involvement at presentation.
DESIGN AND METHODS
Cases were identified from the hematopathology consultation files of the National Cancer
Institute (NCI), Bethesda, MD, USA, between 1996 and 2009. This study was approved
by the NIH Office of Human Subjects Research, and the NCI Institutional Review Board.
Hematoxylin and eosin (H&E) stained sections from all cases were evaluated. Where
available, flow cytometric and cytogenetic results were also reviewed.
In addition, an extensive literature search was performed for published cases of BPDCN,
using its current name as well as former designations, blastic NK-cell lymphoma and
CD4+/CD56+ hematodermic neoplasm, in children under the age of 18 years. Careful
review of the reported immunophenotypes eliminated cases that had been negative for
either CD4 or CD56 (unless positive for CD123), or reported positive for CD34 (which
excludes BPDCN).(1, 28) Coexpression of CD33, CD7, CD2, and/or CD117 was
acceptable, and has been previously described in several cases of BPDCN.(1-4, 28, 35)
The cases were evaluated with respect to clinical features, treatment, and outcome, and
these data were combined with NCI data for comprehensive analysis.
Immunostaining was performed on deparaffinized, formalin-fixed tissue sections using a
panel of antibodies (Table 1). Staining was conducted on an automated immunostainer
(Ventana Medical Systems, Inc., Tucson, AZ).
In situ hybridization
In situ hybridization for Epstein-Barr Virus-encoded RNAs was conducted on formalin-
fixed paraffin sections using the Epstein-Barr Early RNA Probe Reagent-EBER 1-2
(Ventana INFORM EBER, Tucson, AZ) according to the manufacturer’s
recommendations, with appropriate positive and negative controls.
Polymerase chain reaction for T-cell receptor (TCR) gene rearrangements was conducted
using primers to the TCR gamma chain gene.(36) Two separate reactions were carried
out for each extract, with appropriate controls, and the products analyzed by acrylamide
gel electrophoresis, as previously described.(37)
Histologic and Immunophenotypic features
In 8 of 9 NCI cases, the initial diagnostic biopsy was of skin. The neoplastic cells
diffusely infiltrated the superficial dermis, with sparing of the Grenz zone and overlying
epidermis. The malignant cells were small to medium-sized and fairly uniform, with
ovoid to indented or slightly irregular nuclei containing finely dispersed chromatin and
indistinct nucleoli (Figure 1A, Figure 2A). Mitotic figures were observed but generally
not abundant. The cytoplasm was indistinct. Figures 1 and 2 illustrate cases 2 and 4,
Table 2 summarizes the results of our immunohistochemical studies, as well as
immunohistochemical, flow cytometric, and cytogenetic results reported on the 20 cases
identified in the literature. All 9 NCI cases were positive for CD4 and CD123, and all
but 1 (case 6) were positive for CD56. CD68 was negative in all cases, with the
exception of case 7, which showed focal punctate staining. Myeloperoxidase was
negative in cases 1 through 8 (case 9 not tested). All cases were negative for CD3, CD20,
and CD34. In situ hybridization for Epstein-Barr Virus-encoded RNA was negative in all
cases studied (n = 4), as were molecular studies for T-cell clonality (n = 3).
Interestingly, 3 of the 4 pediatric BPDCN cases from the NCI (75%) that were tested for
S-100 expression showed S-100 positivity in the neoplastic cells, typically in a focal or
zonal distribution (Figure 1B). Langerin and CD1a stains were negative, arguing against
Langerhans cell histiocytosis. A retrospective review of a total of 20 additional BPDCN
cases from adults, reviewed at the NCI, demonstrated S-100 expression in 5 (25%).(5) In
contrast, 0 of 28 acute myeloid leukemia (AML) cases expressed S-100. The latter
included 7 cutaneous cases, 18 bone marrow (BM) biopsies, and 3 others, namely central
nervous system (CNS), lymph node, and mesentery (see Supplementary Appendix,
Supplemental Table 1).
Clinical features of NCI and previously published cases
The clinical findings, including initial sites of involvement, treatment modalities, and
outcome data, are summarized in Table 3. Individual NCI cases are described in detail in
the Online Supplementary Appendix. Clinical follow-up was available in 25 of 29 cases
(all patients except for 9, 16, 24, and 26), ranging between 9 months and 13 years
(median, 30 months). Seven of the 29 cases (24%) lacked cutaneous disease at
presentation, with disease confined to BM, peripheral blood, lymph nodes, spleen, and/or
liver. All 7 of these patients survived, with follow-up ranging between 12 and 98 months
(100% survival, median follow-up 60 months). 22 of the 29 (76%) had skin involvement
at the time of presentation, and among the 18 with available clinical follow-up of at least
9 months, 7 patients died (61% survival rate). All patients who lacked cutaneous disease
received acute lymphoblastic leukemia (ALL)-type chemotherapy regimens. Of the 8
patients with initial cutaneous disease who had been treated with ALL-type therapy and
with follow-up available, only 2 died (Patients 5, 6), one of these from therapy-related
Overall, 14 patients in this series initially received ALL-type regimens; 12 achieved
remission and 2 had a partial response. Two of these patients (12, 18) received stem cell
transplantation (SCT), one in CR1 and one in CR2, and both are disease free at last
follow-up. The pediatric cases initially treated with high-risk ALL-type but without SCT
also fared well, with only one reported death (Patient 6), occurring in a child with
relatively advanced disease in the form of a 12 cm cutaneous mass at presentation and
who died of therapy-related complications (described in detail in the Supplementary
Non-Hodgkin lymphoma-type therapy was limited to 6 cases (Patients 1, 2, 5, 15, 21, and
22), 4 of whom survived. Three of these underwent SCT, 1 in CR1 (Patient 15), 1 in
CR1 after receiving ALL therapy (Patient 5), and 1 in CR2 after receiving ALL therapy
(Patient 1). Two of the 3 patients who underwent SCT survived, and 2 of the 3 who did
not undergo SCT survived. All 3 patients who received AML-type chemotherapy died; 1
of progressive disease (Patient 11) and 2 of therapy-related complications (Patients 25,
Among all BPDCN patients who received SCT, the overall survival was 67% (4 of 6
cases), and 2 of these survivors had undergone SCT in second CR. Importantly, the 2
patients who died in spite of SCT had not received initial ALL-type therapy - 1 of the
post-transplant mortalities was disease-related, occurring in a patient who had undergone
SCT in CR1 (Patient 5). The other post-SCT death was attributable to transplant-related
complications (Patient 27).
BPDCN is a rare hematopoietic precursor malignancy that has only recently been
established as a distinct pathologic entity.(38) With a median age at diagnosis of
approximately 65 years, it generally affects older adults and often follows a rapidly fatal
course in spite of a transient initial response to therapy.(1-2, 16) Approximately 85% of
BPDCN cases show cutaneous involvement at presentation, with approximately half the
cases confined to skin at the time of initial staging, whereas leukemic variants lacking
cutaneous involvement have also been documented based on rigorous immunophenotypic
profiling.(1, 4, 20, 23, 30) In adults, the vast majority of patients who achieve CR
subsequently relapse at a median of 9 – 11 months, according to the largest studies.(1-2)
Those patients who relapse typically develop rapid dissemination of disease to BM and
other sites, with CNS involvement in 33% of relapsed cases.(1) While initial response to
therapy may be accomplished with a variety of therapy regimens, sustained remission in
adults has only been described in those who underwent SCT.(16-17, 39) Hence, the
optimal treatment approach in adults appears to justify SCT in first CR and should
include CNS prophylaxis given the high risk of relapse at this site.
To improve understanding of BPDCN in the pediatric age group, we compiled data on 9
cases evaluated at our institution, and in addition critically reviewed the features of 20
previously published cases. In the cumulative series, 24% of pediatric cases lacked
cutaneous involvement at presentation, which is at a slightly higher rate than described in
adults, with disease confined to BM, peripheral blood, lymph nodes, spleen, and/or liver.
Interestingly, all 7 of these patients survived (100% survival, median follow-up 60
months), although only 2 had received SCT. In contrast, only 11 of 18 pediatric cases
associated with cutaneous involvement at presentation and with follow-up available
survived (61%) – only 2 of these 11 survivors had received SCT, and another 2 died in
spite of SCT (1 of disease, 1 of transplant-related complications).
Although cases without initial cutaneous manifestations of BPDCN were associated with
a favorable outcome, direct comparison of cutaneous and extracutaneous-only cases
might be confounded by treatment modalities employed. Namely, all of the patients who
lacked cutaneous disease received ALL-type chemotherapy regimens, which may be
more effective. Hence, the biological significance of variants with or without cutaneous
involvement requires further study. It is important to note that CD123, CD4, and CD56
positivity, the most commonly used BPDCN immunophenotypic profile, is not specific
and that these markers can be expressed in both AML and ALL. However, cases without
cutaneous involvement also expressed other BPDCN markers, including BDCA-4,
CD303/BDCA-2, CD2AP, and TCL1. CD68 is generally negative, but focal punctate
staining is seen in a minority of cases. Strong staining for CD68 should raise suspicion
for acute or chronic leukemia with monocytic differentiation.
A variety of regimens have been employed in the treatment of BPDCN, and some
patients have received multiple therapies, making it difficult to define an optimal
management approach. ALL-type therapies have been most commonly utilized and are
associated with the best-reported results. Unlike adult cases, the pediatric cases in our
review that received high-risk ALL-type therapy experienced favorable outcomes,
DOI: 10.3324/haematol.2010.026179 Download full-text
irrespective of SCT. All patients who received AML-type therapy died (n = 3). Patients
who received non-Hodgkin lymphoma-type therapy appeared to have a favorable
response; however the number of patients treated with this approach was small.
Incorporation of prednisone in the treatment regimen may be critical, as previous studies
have suggested that initial responsiveness to prednisone may serve as a predictor of
favorable prognosis.(23) Furthermore, Rossi et al. hypothesized that intensive
methotrexate dosing may avert subsequent relapse, as the 1 patient who relapsed in their
series of 3 cases had received a less intensive maintenance regimen (Patient 18 in our
meta-analysis).(23) Still, this patient appears cured after undergoing SCT in CR2 (Dr.
Rossi, personal communication).
In determining the role for SCT in first CR for pediatric patients, we reviewed outcome
data with respect to this treatment modality. Among all BPDCN patients who received
SCT, the overall survival was 67% (4 of 6 cases), and 2 of these survivors underwent
SCT in second CR. Importantly, only 1 of the post-transplant mortalities was disease-
related, which occurred in a patient who had undergone SCT in CR1 and had not received
ALL-type therapy; the other death was attributable to transplant-related complications.
The overall survival of patients who did not undergo SCT was 74% (14 of 19 cases).
Thus, the role of SCT in pediatric cases of BPDCN is unclear. Based on our review, our
recommendation for treatment of children with BPDCN would include high-risk ALL
therapy with CNS prophylaxis, reserving SCT for CR2, or to cases where initial
treatment does not induce a rapid or complete remission.