Neoplasias)de)células)dendrí1cas)plasmocitoides)blás1cas.) Dr#San'ago#Montes#Moreno## Servicio#de#Anatomía#Patológica#HUMV.#
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1 Neoplasias)de)células)dendrí1cas)plasmocitoides)blás1cas.) Dr#San'ago#Montes#Moreno## Servicio#de#Anatomía#Patológica#HUMV.#
2 )Clinical)features:)) ) 61#year#old#male#with#mul'ple#cutaneous# nodules#in#the#thorax#and#upper#extremi'es.#the# pa'ent#also#had#mul'ple#lymphadenopathies#in# cervical,#supraclavicular,#axillary,#inguinal#regions,# bone#marrow#and#csf#involvement.##
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10 CD33-, MPO-, CD117-, CD34-, CD13-, CD19-, CD3-, CD3C-, CD2-, CD8-, CD5-, CD7-, CD15-.
11 )Proposed)Diagnosis:# #Blas'c#plasmacytoid#dendri'c#cell#neoplasm#(WHO) 1# # AOer# diagnosis# the# pa'ent# achieved# CR# aoer# HYPER# CVAD# S MTX+ARAC# DA# X6# and# underwent# autologous# stem# cell# transplanta'on.# # The# pa'ent# is# alive# without# evidence# of# disease#33#months#aoer#the#ini'al#diagnosis.# 1 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.;2008
12 )Defini1on:# #Blas'c#plasmacytoid#dendri'c#cell#neoplasm#(WHO) 1 #is#a#clinically# aggressive# tumour# derived# from# the# precursors# of# plasmacytoid# dendri'c# cells# (plasmacytoid# monocytes# and# professional# type# 1# interferon# producing# cells).# This# type# of# neoplasm# has# a# high# frequency# of# cutaneous# and# bone# marrow# (BM)# involvement# and# leukemic#dissemina'on.# # Synonyms:# Blas'c# NKScell# lymphoma,# agranular# CD4+natural# killer# cell# leukemia,# blas'c# natural# killer# leukemia/lymphoma,# agranular# CD4+CD56+# haematodermic# neoplasm/tumour.# #Epidemiology:#BPDC#is#a#rare#haematologic#neoplasm#without#any# known# racial# or# ethnic# predilec'on.# It# has# a# male/female# ra'o# of# 3.3:1#to#7.25:1#according#to#the#series 1,2.#Most#pa'ents#are#elderly# (mean#age#61#y)#but#it#can#occur#at#any#age,#including#childhood 3.# 1 F. Facchetti, DM Jones, T Petrella. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.; Carlo Cota et al. Cutaneous Manifestations of Blastic Plasmacytoid Dendritic Cell Neoplasm- Morphologic and Phenotypic Variability in a series of 33 patients.am J surg Pathol 2010-, 1 (34): Jegalian AG, et al. Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications. Haematologica 2010; 95 (11):
13 )Clinical)features:)) )Clinical#onset#with#generalized,#localized#(mul'ple)#or#solitary# macules,#plaques#and#or#tumors 1,2.# # Regional# lymphadenopathy# at# presenta'on# is# common# (20%) 1.#Cytopenias#and#splenomegaly#can#occur#at#diagnosis 4.# PB# and# BM# involvement# can# be# minimal# or# absent# at# presenta'on# (13S60%# in# larger# series 2,4 )# but# invariably# develops#with#progression#of#disease.## (2) 1 F. Facchetti, DM Jones, T Petrella. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.; Carlo Cota et al. Cutaneous Manifestations of Blastic Plasmacytoid Dendritic Cell Neoplasm- Morphologic and Phenotypic Variability in a series of 33 patients.am J surg Pathol 2010-, 1 (34): Feuillard J, et al. Clinical and biologic features of CD4+CD56+ malignancies. Blood 2002; 1 (99):
14 )Clinical)features:)) ) The# prognosis# is# rapidly# fatal# in# the# absence# of# treatment.# Albeit#a#good#ini'al#response#(78%#CR 4 )#to#polychemotherapy,# elderly# pa'ents# invariably# relapse# in# less# than# 2# years 4,5,# mainly#in#the#bone#marrow,#skin#and#central#nervous#system 4.# Overall#the#outcome#is#very#poor#with#an#average#survival#of# 14#months#(range#1S40#m,#variable#according#to#age) 3,5. ## # Associa'on# with# other# myelodysplas'c/myeloprolifera've# disorders#at#diagnosis#or#during#progression#(mml,#aml) 4,#5,#6.#) Differen'al# diagnosis# with# massive# mature# (CD56S)# and# blas'c# plasmacytoid#dendri'c#cell#tumors#s#cmml#related 7.# 4. Feuillard J, et al. Clinical and biologic features of CD4+CD56+ malignancies. Blood 2002; 1 (99): Petrella T, et al. Blastic NK-Cell Lymphomas (Agranular CD4+CD56+Hematodermic Neoplasms). Am J Clin Pathol 2005;123: Herling et al. TCL1 expression in plasmacytoide dendritic cells (DC2s) and the related CD4+CD56+ blastic tumors of skin. Blood 2003; 101: Vitte et al. Specific skin lesions in chronic Myelomonocytic Leukemia. Am J Surg Pathol Am J Surg Pathol 2012;36:
15 )Histopathological)and)phenotypical)features:)) ) Histopathological) paderns:) diffuse# dermal,# perivascular/ periadnexal,# # inters''al.# Grenz# zone,# rare# cases# may# show# papillary# dermal# involvement# and# epidermotropism 2.# Angiotropism# can# be# found# without# angiodestruc'on# or# coagula've#necrosis 1,2.) ) Minimal) immunophenotypic) criteria:) coexpression) of) CD4,) CD56,)CD123)and)TCL1)in)the)absence)of)B,)T)and)myeloid/ myelomonocy1c) cell) lineage) markers 1,) 5,6.) However,# phenotypic# variability# exists# and# some# cases# lack# 1# or# 2# of# 4# markers# (34%# of# cases;# CD4S# (20%),# CD56S# (8.9%),# CD123# (4.4%),#TCL1S#(10.2%)) 2.# # Other# markers:# CD68# (dot# like# staining# in# a# minority# of# cases 1,2 ),# TdT# (1/3# cases 1 ),# BCL2# 2,# CD7,# BDCA2,# CD101,# BDCAS4,#IRFV8,)BCL11A,#CD2AP 8) 1 F. Facchetti, DM Jones, T Petrella. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.; Carlo Cota et al. Cutaneous Manifestations of Blastic Plasmacytoid Dendritic Cell Neoplasm- Morphologic and Phenotypic Variability in a series of 33 patients.am J surg Pathol 2010-, 1 (34): Petrella T, et al. Blastic NK-Cell Lymphomas (Agranular CD4+CD56+Hematodermic Neoplasms). Am J Clin Pathol 2005;123: Herling et al. TCL1 expression in plasmacytoide dendritic cells (DC2s) and the related CD4+CD56+ blastic tumors of skin. Blood 2003; 101: Marafioti et al. Novel markers of normal and neoplastic human plasmacytoid dendritic cell neoplasms. Blood 2008; 111:
16 A Parra Cubillos et al, USCAP 2013
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19 Phenotypic Variability in BPDCN 29/45 (64%) express all 4 markers (TCL1, CD123, CD56, CD4). 11/45 (24%) lack 1 marker (8 cases CD4, 2 cases CD56, 1 case TCL1). 3/45 (6%) lack 2 markers. 2/45 (4%) lack 3 markers. CD4- (12/45:26%), CD56- (5/45:11%), CD123- (4/45: 8%), TCL1- (2/45: 4%). SPI-B protein expression in BPDCN and its cutaneous mimickers S Montes Moreno et al, Blood 2013
20 SPI-B protein is overexpressed in Blastic Plasmacytoid Dendritic Cell Neoplasms
21 )Gene1cs)/Molecular)features) )Complex#karyotypes#with#chromosomal#abnormali'es#in#70%#of#the#cases#(5q,#6q,# 9,# 12p,# 13q# and# 15q) 1.# Recurrent# dele'ons# in# 4q34# and# 13q12Sq31# (with# downregula'on#of#rb1#and#lats2#and#overexpression#of#hes6,#runx2,#flt3) 9.# # Dele'ons# of# chromosome# 9,# 13,# par'al# loss# affec'ng# 17p# or# 12p# lead# to# combina'ons#of#dele'ons#of#tumor#suppressor#genes#rb1,#cdkn1b,#cdkn2a#and# TP53 10.# Loss#of#CDKN1B#locus#and#p27#protein#expression#(64%),#loss#of#CDKN2AS ARFSCDKN2B#locus#(9p21.3)#in#50% 11,#and#66% 12 #with#loss#of#p16#func'on.## # Disrup'on# of# G1/S# transi'on# and# biallelic# loss# of# 9p21.3# as# a# marker# of# poor# outcome 12.) ) Primary) acquired) soma1c) muta1ons) in) TET2) (53%)) and) secondary ) TP53) muta1ons)(38%) 13.) 9. Dijkman R, van Doorn R, Szuhai K, Willemze R, Vermeer MH, Tensen CP. Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities. Blood. 2007;109(4): Jardin et al. Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+ haematodermic neoplasms and contribute to the aggressiveness of the disease. Leukemia Apr;23(4): Wiesner T et al. Alterations of the cell-cycle inhibitors p27(kip1) and p16(ink4a) are frequent in blastic plasmacytoid dendritic cell neoplasms. J Invest Dermatol Apr;130(4): Lucioni M et al. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion. Blood Sep 7. [Epub ahead of print] 13. Jardin F et al. TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm. Br J Haematol May;153(3):413-6.
22 BPDCN coding genome Primary acquired somatic mutations in: - - TET2 (36%) ASXL1 (32%) - NRAS (20%) - - NPM1 (20%) IKAROS (20%) - ZEB 2 (16%) 14. J Menezes et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasms. Leukemia 2013 Sept 27 (epub)
23 )Clinical)features:,)OUTCOME,)poten1al)treatments:) S BPDCN#has#unusual#resistance#to#conven'onal#chemotherapy.# S Treatment# based# on# ALLStype# regimens# or# AMLStype# regimens 14.# High# dose# therapy# followed# by# allossct# can# provide#durable#disease#control 14, # 15.# 15. L Pagano etal. Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an italian multicenter study. Haematologica (2). 16. D Roos-Wellet al. Stem cell transplantation can provide durable disease control in blastic plasmacytoid dendritic cell neoplasm: a retrospective study from the European Group for Blood and Marrow Transplantation. Blood. 2013;121(3):
24 Ref) Treatment) N) CR)rate) Relapse) Median)OS) Notes) Feuillard#J#et#al,#2002# ALLStype## AMLStype# Pallia've/none# Total# 15#(23)# 6#(23)# 2#(2/23)# 23# 12# 6# 0# 18#CR#(86%)# 15/18#(83%)# 12#(3S96)# Adult#and#pediatric# popula'on# Jegalian#AG,#et#al,#2010# ALLStype# 9# 8)CR)(89%)) 1/8#(12%)# 23#(1S156)# Pediatric)popula1on) Tsagarakis#NJ#etal,#2010# ALLStype# AMLStype# Pallia've/unk# Total# 13# 6# 3# 22# 12#CR# 3#CR# 0# 15#CR#(79%)# 6/15#(40%)# 15#(6,6# #23,4)# Adult#popula'on# Dalle#S,#et#al,#2010# ALLStype# AMLStype# Radiotherapy# Pall/none# Total# 26# 12# 5# 4# 47# 14#CR# 5#CR# 4#CR# 0# 23#CR#(53%)# n.r# 16,7#(1S54)# Adult#and#pediatric,# only#cutaneous# involvement#included.# Hashikawa#K,#et#al,#2011# ALLStype# AMLStype# Radiotherapy# None/unk# Total# 13# 4# 4# 5# 26# 10#CR# 1#CR# 3#CR# n.r# 14#CR#(67%)# 11/14#(78%)# 12,7#(1S42)# Adult#and#pediatric,# only#cutaneous# involvement#included.# Dietrich#S#et#al,#2011# ALLStype# AMLStype# Total# 4# 2# 6# 4#CR# 1#CR# 5#CR#(83%)# 4/5#(80%)# 21#(6S82)# Adult#popula'on# Pagano#et#al#2013# ALLStype# AMLStype# AlloVSCT) Total# 15# 26# 6# 43# 10#CR# 7#CR# 17#CR#(39%)# 6/17#(35%)# 12,3#(1S32,9)# 7,1#(0,2S19,5)# 22,7)(12V32,9)) Adult#pa'ents# Roos#Weill#et#al,#2013# ALLSor#AMLStype# NHLStype# AlloVSCT) Auto#SCT# 27# 7# 34# 5# 19#CR# 11/34#(32%)# 28)(4V77)) Adult#pa'ents.#Median# age#41#years#
25 CONCLUSIONS) Blas'c# plasmacytoid# dendri'c# cell# neoplasm# (WHO)# is# a# clinically# aggressive# myeloid# neoplasm# derived# from# the# precursors# of# plasmacytoid# dendri'c# cells.# This# type# of# neoplasm# has# a# high# frequency# of# cutaneous# and# bone# marrow# (BM)# involvement# and# leukemic#dissemina'on.# Diversity# in# the# # histopathological# paoerns# of# skin# infltra'on.# Minimal# immunophenotypic# criteria:# coexpression# of# CD4,# CD56,# CD123#and#TCL1#in#the#absence#of#B,#T#and#myeloid/myelomonocy'c# cell#lineage#markers.#significant#phenotypic#variability.# Recurrrently# mutated# genes# include# TET2,# ASXL1,# NRAS,# NPM1,## IKAROS,# ZEB2# (DNA# methyla'on# and# chroma'n# remodelling# pathways).# Treatment# based# on# ALLStype# regimens# # and# high# dose# therapy# followed#by#allossct#can#provide#durable#disease#control.##
26 Ex-LYMPHOMA GROUP, CNIO. GRUPO DE GENÓMICA DEL CANCER. UNIDAD DE CITOGENETICA HEMATOLOGICA, HUMV: Ana Batlle, Sonia Gonzalez de Villambrosía SERVICIOS DE HEMATOLOGÍA Y PATOLOGIA, HUMV: Eulogio Conde, Andrés Insunza, Francisco Mazorra BIOBANCO HUMV/IFIMAV Laura Cereceda, José Revert Arce.
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