The Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasms Presenting Leukemia Dissemination, Diagnosed By Nation-Wide Immunophenotyping for Pediatric Hematological Malignancy in Japan
Authors: Deguchi Takao , Kiyokawa Nobutaka , Hashii Yoshiko , Saito Akiko M. , Manabe Atsushi , Horibe Keizo , Komada Yoshihiro 
Published: November 2019

Abstract
[Background] According to the nation-wide retrospective study for pediatric leukemia phenotyping, immunological diagnostic committee of Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) established diagnostic criteria and panel to pediatric hematological malignancies in 2008. Then Nation-wide standardized central immnophenotyping in Japan was started from 2011, and done in more than 2,500 cases by the end of 2014. Most cases were determined immunological diagnosis, but it was of note that we found 11 acute unclassified leukemia cases, including typical and atypical blastic plasmacytoid dendritic cell neoplasms (BPDCN). BPDCN is a rare subtype of leukemia/lymphoma, which has been categorized in the 2008 World Health Organization (WHO) classification of hematological diseases under acute myeloid leukemia and related precursor neoplasms. It was well known for high incidence of extra medullary regions. Most cases of BPDCN were found in elder people, so pediatric cases were extremely rare. We report here the characteristics of pediatric BPDCN cases, including clinical manifestations and peculiar immunophenotype.
[Materials and Methods] Immunophenotyping was done on bone marrow (BM) aspiration samples according to diagnostic panel and criteria established by JPLSG immunological diagnostic committee. Immunophenotyping data from July 2011 to June 2015 were collected from JPLSG immunophenotyping centers and analyzed. BPDCN cases were screened by typically CD4+ 56+ HLA-DRhi profile. Other lineage markers such as CD7, CD34, CD13, CD33, CD36, CD64, CD123, and NG2 were also analyzed. As it is well known that existence of atypical phenotype in a substantial proportion, including absence of CD56 and/or CD4, immunophenotype data were prudently investigated and compared with 21 acute myelogenous leukemia (AML) presenting M5 characteristics in FAB criteria.
[Result] Out of more than 2,500 cases, 4 cases were diagnosed as typical BPDCN (CD4+ 56+ HLA-DRhi), and 2 atypical BPDCN (1 CD56-, 1 CD4-) by immunophenotyping. All 6 cases presented leukemic dissemination, but only 4 typical cases indicated extra medullary regions. Gender ratio (M: F) was 3:1 and 0:2, and median age were 6.9 years (3.3 to 11.3) and 13.8 (12.8, 14.7) respectively. All 6 cases were negative for CD34 and CD13, and positive for NG2. CD123 was also positive in all (5/5) cases. CD33 and CD36 were positive in 5 cases respectively. It was of note that CD64, typical monocytic marker, was negative in all 6 cases although it was positive in all AML-M5 cases. All BPDCN cases could be distinguished with expression patterns of NG2, CD7, CD33, CD36 (positive) or CD13, CD64 (negative). Additionally, CD2 was positive in 3/6 cases, TdT was positive in 2/6 cases. CD117 was positive in 2 cases (1 typical, 1 atypical).
[Discussion] BPDCN is a rare, clinically aggressive hematologic malignancy that most commonly manifests as cutaneous lesions with or without bone marrow involvement and leukemic dissemination. Diagnosis of BPDCN has been usually made by histopathologic examination with cutaneous lesions, which is typically positive for interleukin-3 receptor (CD123), blood dendritic cell antigen 2 (BDCA2)/CD303, and TCL-1. Morphologic and immunophenotypic studies were usually performed on BM and/or peripheral blood prior to histopathologic examination, however diagnosis with these examinations as BPDCN is not so easy because of the lack of morphological peculiarity or traditional lineage-specific markers. Treatments for BPDCN patients have been also inconsistent, because there are no prospective clinical trial data to define the optimal frontline treatment. AML-like or acute lymphoblastic leukemia (ALL)-like regimens have been used for induction therapy, as well as lymphoma-like regimens. The difficulty of BPDCN diagnosis might affect to choose inconsistent frontline therapy. Recently some reports documented ALL oriented therapy indicated more effectiveness to BPDCN, so the diagnosis should be made precisely to evaluate the treatment effectiveness. Here we indicated new diagnostic strategy by immunophenotyping with NG2, CD7, CD33, CD36, CD13, and CD64 as well as CD4, CD56 and HLA-DR. This approach contributes not only to select treatment regimen but also to investigate molecular pathogenesis such as whole exome sequence.

Disclosures
No relevant conflicts of interest to declare.