Journal of the Louisiana State Medical Society
Table 3: Summary of the most frequent genomic alterations in BPDCN Change Chromosome Cytoband
% of patients
Candidate genes
Loss Loss Loss Loss Loss Loss Loss Loss Loss Loss Loss
13 12
q12.11-q34
50-78 50-67 50-66 50-55 21-44 33-36
RB1
p13.2 p21.3
CDKN1B, ETV6
9 9 5
CDKN2A, CDKN2B, MTAP
q34
NOTCH, TRAF2, CARD9
q23.1-a35.2 q11.2-a26.3 p22.2-p21.1 p13.4-p13.2 p13.3-p11.2 p22.3-p22.1
SMAD5, MSH3, MCC, APC
15
CYP1A1
3
29
PTPN23
19 17
22-29
CDKN2D, PRKCSH
22 21
TP53
7 6
MAD1L1
q23.3-q27
11-21
PARK2
Table 3: Summary of the most frequent genomic alterations in BPDCN. Adapted from ref. 25. BPDCN, blastic plasmacytoid dendritic cell neoplasm; CDKN, cyclin-dependent kinase inhibitor; MTAP, methylthioadenosine phosphorylase; TRAF2, tumor necrosis factor receptor-associated factor 2; CARD9, caspase recruitment domain; RB1, retinoblastoma tumor suppressor gene; CYP1A1, cytochrome P450 family 1 subfamily a polypeptide 1; PRKCSH, protein kinase C substrate 80K-H; PTPN23, protein- tyrosine-phosphatase-n23; MCC, mutated in colorectal cancer; APC, adenomatous polyposis coli tumor suppressor gene; PARK2, Parkinson protein 2; MAD1L1, mitotic arrest deficient-like 1; TP53, tumor protein 53. 9,12,24,25
of 5 (80%) T-ALL cases. 6 Therefore, it has been suggested that immunophenotypic analysis using a panel of antibodies including CD4, CD56, and at least 2 PDC-associated antigens (such as CD123, TCL1, BDCA2, CD2AP, and BCL11A), as well as specific markers to rule out other lineages, should be performed to confirm the diagnosis. Genetics Genetic studies are limited for BPDCN, and no defin- ing recurrent genetic abnormalities have been identified. BPDCN was shown to be associated with normal karyo- type 8,10,11,17 and variable genomic changes by conventional cytogenetic analysis, comparative genomic hybridization (CGH) and PCR. 9,12,24,25 The most frequent genomic altera- tions in BPDCN are summarized in Table 3. 9,12,24,25 Lucioni et al. showed deletion of 9p21.3 containing CDKN2A (en- coding p16-INK4a) and CDKN2B was found in 14 out of 21 (66.6%) patients and represented a worse prognosis factor (median overall survival of 11 months for homozygous loss versus 26 months for hemizygous loss). 9 Interestingly, Petrella et al. (2012) reported an 82-year-old male patient had normal karyotype on bone marrow specimen by con- ventional cytogenetic analysis; losses of chromosome 6, 12 (CDKN1B and ETV6), and 13 on skin biopsy specimen and additional losses of chromosome 2 and 5 on bone marrow specimen by CGH; loss of 2p, 5q, 12p (ETV6), and 13q but not 17 (TP53) on bone marrow specimen; and loss of ETV6 on snap-frozen skin sections by FISH analysis, suggesting that the difference in CGH results between skin and bone marrow specimens may reflect genomic alterations as-
sociating with progression of the disease. Other sporadic genomic aberrations include loss of 1p31.3-33 (containing CDKN2C/p18) and gain of 16p/q, loss of 6q and 7p, t(1;6), t(9;22), t(11;19)(q23;p13.3), trisomy 7, gain of 9p24 and loss of 11q22, and loss of Y. Jardin et al. showed that TET2 (ten eleven translocation 2) and TP53 mutation were seen in 54% and 38% of BPDCN patients by using PCR. 12 Additionally, Wiesner et al. demonstrated that expression of cell cycle inhibitor p27 KIP1 (encoded by CDKN1B) and p16 INK4a (encoded by CDKN2A) was downregulated in tumor cells. 25 These findings suggest that loss of tumor suppressor genes such as CDKN1B, CDKN2A, ARF, CDKN2B, RB1, and TP53, and resultant functional loss of cell cycle checkpoint control- ling proteins, may lead to dysregulation of G1/S transition of the cell cycle and tumorigenesis. To the best of our knowledge, this is the first case of BPDCNwith central nervous system involvement as initial presentation since the latest WHO classification in 2008. Dermatologists and dermatopathologists should be aware of this rare disease for which nearly half of the patients present with only cutaneous lesions at diagnosis. The diagnosis of BPDCN is generally based on the skin biopsy and immu- nophenotypic analysis. High-dose chemotherapy followed by allogeneic SCT in first remission has been suggested to provide durable remission and favorable survival. REFERENCES 1. Chan JKC, Jaffe ES, Ralfkiaer E. Blastic NK-cell lymphoma. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC, Lyon .
8 J La State Med Soc VOL 166 January/February 2014
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