Blastic plasmacytoid dendritic cell neoplasm (BPDCN)

Disease derives from precursors of plasmacytoid dendritic cells.

The t(6;8) has been found in a limited subset of BPDCN: Less than 10 cases reported to date. Preponderance of male cases (7/8 to date). Average age 65 years, in keeping with BPDCNs mean/median age of 61-67 (WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, 2017).

In general, BPDCN is an aggressive disease that most commonly involves the skin but can also infiltrate the bone marrow and peripheral blood as well as the lymph nodes. Seven out of eight cases of t(6;8) reported so far had bone marrow involvement based on bone marrow biopsy (Boddu et al., 2018; Momoi et al., 2002; Takiuchi et al., 2012; Nakamura et al., 2015; Fu et al., 2013; personal communication). One case reported by Leroux et al. in 2002 showed an extensive peripheral blood involvement with 95% circulating blasts. Although a bone marrow biopsy was not performed, the heavy involvement of peripheral blood, indicating bone marrow involvement, was sufficient to make the diagnosis.

Found with additional abnormalities in all cases, as the sole abnormality in the stemline in one case (Boddu et al., 2018), as a secondary abnormality in one case (Boddu et al., 2018), as part of a complex karyotype in 5/8 cases.
Table 1: Cases of BPDCN with t(6;8)(q21;q24)

Reference	Age	Sex	Site involved	Karyotype
Momoi et al. 2002	69	M	BM, Skin	46, XY, add(5)(q11), add(5)(q31), t(6;8)(p21,q24),del(13)(q12q14),add(15)(q13)
Boddu et al. 2018	60	M	BM, Skin, LN	46,XY,del(13)(q12q22)[16]/46,idem,t(6;8)(p21;q24.1),del(14)(q24q32)[2]/46,idem,t(6;8)(p21;q24.1),del(14)(q24q32)[cp2]
Boddu et al. 2018	71	M	BM, Skin	46,XY,t(6;8)(p21;q24.2)[5]/47,idem,+18[11]/46,XY[4]
Takiuchi  et al. 2012	74	M	BM, spleen	47, XY, t(6;8)(p21;q24),+r
Nakamura et al. 2015	81	M	BM, Skin, LN	47,X,-Y t(6;8)(p21;q24),+add(7)(p11.2),+der(8)t(6;8),+20[17/20], 46,XY[3/20] among LN cells; 48,X,Y,t(6;8)(p21;q24),+add(7)(p11.2),+der(8)t(6;8),+2[5/13],49,idem,+mar1[2/13],49,idem,der(8)t(6;8),?t(9;15)(p22;q15),+mar1 2/13]/46, XY[3/13]
Fu et al. 2013	67	F	BM, LN	46,XX,del(5)(q13q33),t(6;8)(p21;q24)
Leroux et al. 2002	74	M	PB (BM not performed)	49,XY,+add(6)(q21),-8,+2mar,+r[6]/49,idem,t(15;16)(?q21;?q21)[6]/49,idem,t(3;5)(?q21;?q31)[5], ish wcp M-FISH 49,XY,+6,t(6;8)(p21;q24),+r(12),+20/49,idem,inv(15)(q1?4q2?3),t(16;16)(q?;q?)/49,idem,t(3;5)(q?21;q?31)[13]
Personal communication	29	M	BM, PB	44-45,X,-Y,del(1)(p12p22),t(6;8)(p21.1;q24.2)[cp5]/46,XY[1].nuc ish(MYCx2)(5MYC sep 3MYCx1)[54/100]

BM: bone marrow, LN: lymph node, PB: peripheral blood.
Of note, cytogenetic abnormalities are present in about two-thirds of BPDCN cases, involving chromosomes 5q34, 12p13, 13q13-21, 15q, and loss of chromosome 9 (WHO Classification of Tumours of hematopoietic and lymphoid tissues, 2017).

The prognosis of BPDCN is usually poor in adults (Bekkenk et al., 2004, Suzuki et al., 2005) and this appears to be true for cases with t(6;8). Two cases with this translocation failed to respond to treatment, the overall survival being 3 and 12 months respectively (Boddu et al., 2018). One patient relapsed three months after the initial diagnosis and treatment and received multiple lines of chemotherapy but eventually died because of septic shock nine months after the initial diagnosis (Momoi et al., 2002). The only female reported so far with t(6;8) received palliative chemotherapy and died two months after the initial diagnosis. Another patient responded to treatment and tumor cells in the peripheral blood disappeared in day 8; however, the patient died of septic shock on day 16 (Takiuchi et al., 2012). A 29-year-old male patient who was diagnosed with BPDCN with complex karyotype including t(6;8) received ALL-based chemotherapy achieved complete morphological remission by day 24 of treatment and has been on sustained remission at least until this paper was written (personal communication).

The t(6;8)(p21.1;q24.2) is identified by conventional karyotyping.
Note: Other translocations involving 8q24 have been reported in BPDCN: t(8;14)(q24;q32), t(X;8)(q24;q24), t(3;8)(p25;q24) (Boddu et al., 2018; Nakamura et al., 2015)

The translocation has been shown to result in a split MYC signal when using a commercial MYC break-apart FISH probe (Nakamura et al., 2015, Boddu et al., 2018, Fu et al., 2013). Involvement of the MYC gene has also be inferred from the positive MYC immunochemistry observed on bone marrow slides (Nakamura et al., 2015, Boddu et al., 2018). Molecular analysis of the 8q24 breakpoint showed that it occurred in the PVT1 gene on chromosome 8 (Nakamura et al., 2015; Fu et al., 2013; Jardin et al., 2009). PVT1 is located 149 kb telomeric to MYC. It is a long non-coding RNA located within the interval between the 5 MYC probe and 3MYC commercial probes used to identify MYC rearrangements. Jardin et al. in 2009 found, in BPDCN, a 5.6-Mb interstitial deletion on 8q24 involving PVT1 bringing MYC oncogene adjacent to miR-30b/30c leading to possible up-regulation of these genes.

MYC/SUPT3H