linfoma di hodgkin

Linfoma di HodgkinLinfoma di Hodgkin

Thomas HodgkinThomas Hodgkin circa 1835circa 1835born 1798 born 1798 PentonvillePentonville, , LondonLondonQuaker familyQuaker family1825 lecturer in morbid 1825 lecturer in morbid anatomy and curator of the anatomy and curator of the museum Guymuseum Guy’’ssfellow members of stafffellow members of staff-- Richard BrightRichard Bright-- Thomas AddisonThomas Addison

The Man:The Man:

paper first read before thepaper first read before theMedicoMedico--ChirugicalChirugical Society of Society of London,London, January 10th 1832January 10th 1832

6 cases from Guy6 cases from Guy’’s Museum s Museum and 1 from UCHand 1 from UCH

““enlargement of the glands enlargement of the glands appeared to be a primitive appeared to be a primitive affection of those bodies, affection of those bodies, rather than the result rather than the result of an irritation... from some of an irritation... from some ulcerated surface or other ulcerated surface or other inflamed texture.inflamed texture.””

The Disease:The Disease:

1926 Fox1926 Fox examined 3 cases examined 3 cases microscopically:microscopically:2 were Hodgkin2 were Hodgkin’’s Diseases Disease

1986:1986:2 cases immunostained for 2 cases immunostained for CD15CD15

The Disease:The Disease:

1823 met 1823 met MontefioreMontefiore family family when medical studentwhen medical studentbecame lifelong friend with became lifelong friend with MosesMoses

PhilanthropyPhilanthropy: worked : worked increasingly for poor and increasingly for poor and oppressed (e.g.1838oppressed (e.g.1838--aborigineaborigine’’s protection)s protection)

1863: travelled to Morocco 1863: travelled to Morocco with Moses to intercede with with Moses to intercede with Sultan on behalf of Christians Sultan on behalf of Christians and Jews thereand Jews there

The Mission:The Mission:

The Final Mission:The Final Mission:1865: locusts and cholera decimating Jerusalem1865: locusts and cholera decimating JerusalemJewish board of deputies and Jewish board of deputies and MontefioreMontefiore collect collect ££3,000 3,000 for Holy Land Relieffor Holy Land Relief

1866: 1866: MontefioreMontefiore and Hodgkin set out for Jerusalemand Hodgkin set out for Jerusalem

Hodgkin died of Hodgkin died of dysentery or cholera dysentery or cholera 4th April 1866 aged 684th April 1866 aged 68

buried in the English buried in the English cemetery at Jaffacemetery at Jaffa

Caratteristiche morfologicheCaratteristiche morfologiche

Il LH mostra tipici elementi Il LH mostra tipici elementi pluripluri--nucleati, con nucleati, con ∅∅=60 =60 μμm e m e nucleoli nucleoli similsimil--inclusionaliinclusionali, , talora acidofili (cellule di Reedtalora acidofili (cellule di Reed--Sternberg o diagnostiche). Sternberg o diagnostiche). Le varianti mononucleate sono Le varianti mononucleate sono chiamate cellule di Hodgkin.chiamate cellule di Hodgkin.Tali cellule assumono carattere Tali cellule assumono carattere ““diagnosticodiagnostico”” in un in un pabulumpabuluminfiammatorio. infiammatorio.

Carl Sternberg 1898Carl Sternberg 1898

Dorothy Reed 1902Dorothy Reed 1902

Caratteristiche morfologicheCaratteristiche morfologiche

Il LH mostra tipici elementi Il LH mostra tipici elementi pluripluri--nucleati, con nucleati, con ∅∅=60 =60 μμm e m e nucleoli nucleoli similsimil--inclusionaliinclusionali, , talora acidofili (cellule di Reedtalora acidofili (cellule di Reed--Sternberg o diagnostiche). Sternberg o diagnostiche). Le varianti mononucleate sono Le varianti mononucleate sono chiamate cellule di Hodgkin.chiamate cellule di Hodgkin.Tali cellule assumono carattere Tali cellule assumono carattere ““diagnosticodiagnostico”” in un in un pabulumpabuluminfiammatorio. infiammatorio.

1 1 –– 3% cellularit3% cellularitàà

rosetterosetteTT

eosinofilieosinofili endoteliendoteli plasmacelluleplasmacellule midollo osseomidollo osseo

fibroblastifibroblastilinfociti Tlinfociti T

ILIL--99

ILIL--55 ILIL--1, TNF1, TNF

ILIL--1, TNF1, TNF

MM--CSFCSFGG--CSFCSF

ILIL--66

Fenomeni Fenomeni autocriniautocrini e paracrinie paracriniILIL--44 ILIL--88

LGCBD con cellule RSLGCBD con cellule RS--similisimili

Liposarcoma infiammatorioLiposarcoma infiammatorio

Cellule RSCellule RS--similisimili

IstogenesiIstogenesi

Allo stato dellAllo stato dell’’arte, esiste unanimitarte, esiste unanimitàà di di pareri circapareri circa

la natura linfoide delle cellule la natura linfoide delle cellule neoplastiche del LH.neoplastiche del LH.

HaraldHarald SteinStein

Nature 1982; 299:65Nature 1982; 299:65--7.7.Blood 1985; 66:848Blood 1985; 66:848--58.58.Am J Pathol 1987; 128:390Am J Pathol 1987; 128:390--3.3.Blood 1989; 74:1678Blood 1989; 74:1678--89.89.Cell 1992; 68:421Cell 1992; 68:421--7.7.Cancer Res 1994; 54:2873Cancer Res 1994; 54:2873--7.7.NEJM 1995; 333:901NEJM 1995; 333:901--66NEJM 1997; 337:453NEJM 1997; 337:453--8.8.J Pathol 2000; 190:613J Pathol 2000; 190:613--8.8.Blood 2000; 95:3020Blood 2000; 95:3020--4.4.Blood 2000; 96:1889Blood 2000; 96:1889--99.99.Blood 2000; 96:3681Blood 2000; 96:3681--95.95.Blood 2001; 97:496Blood 2001; 97:496--501.501.Blood 2002; 99:3060Blood 2002; 99:3060--2.2.Blood 2002; 99:3398Blood 2002; 99:3398--403,403,J Exp Med 2002; 196:605J Exp Med 2002; 196:605--17,17,J Pathol. 2004; 202:60J Pathol. 2004; 202:60--9,9,J Exp Med. 2004;199:1041J Exp Med. 2004;199:1041--52,52,Blood. 2004;104:3326Blood. 2004;104:3326--34. 34.

vacuumvacuum

Single cell PCRSingle cell PCR

ExtrathymicExtrathymic perivascular perivascular spacespace

Thymic folliclesThymic follicles

CD23CD23+ + asteroid Basteroid B--cellscellsMedullary B lymphocytesMedullary B lymphocytes

Fend F et al, Fend F et al, VirchowsVirchows Arch B 60:381, 1991.Arch B 60:381, 1991.TCL1TCL1--, CD27, CD27++: : RemottiRemotti D et al. J Clin D et al. J Clin PatholPathol ((SupplSuppl), 2002.), 2002.CD23CD23++: : CalaminiciCalaminici MR et al, Histopathology 45:619, 2004.MR et al, Histopathology 45:619, 2004.

Thymus: normal B lymphocytesThymus: normal B lymphocytes

CD20CD20CD20CD20

CD20CD20

SeitzSeitz V et al. V et al. BloodBlood 2000; 95:30202000; 95:3020--44

Linfoma di Hodgkin:Linfoma di Hodgkin:attuale inquadramento attuale inquadramento

classificativoclassificativo

LH a prevalenza linfocitaria (4LH a prevalenza linfocitaria (4--5%)5%)

NodulareNodulare DiffusaDiffusa(80%) (80%) (20%)(20%)

Prevalenza linfocitaria nodularePrevalenza linfocitaria nodulare

Caratteri cliniciCaratteri clinici**:: distribuzione unimodale per etdistribuzione unimodale per etàà((picco a 40 annipicco a 40 anni),),diffusione simile ai LNHdiffusione simile ai LNH, , decorso indolentedecorso indolente,,ricadute tardive (a 10 e piricadute tardive (a 10 e piùù anni),anni),occasionale evoluzione in LGCBDoccasionale evoluzione in LGCBD. . ##

** EkstrandEkstrand BC & BC & HorningHorning SJ. Curr Oncol SJ. Curr Oncol RepRep 2002; 4:4242002; 4:424--33.33.## Ohno T et al. Am J Clin Pathol 2001; 116:506Ohno T et al. Am J Clin Pathol 2001; 116:506--11; Huang JZ et al. Leuk 11; Huang JZ et al. Leuk

Lymphoma 2003; 44:1903Lymphoma 2003; 44:1903--20.20.

LH,PL nodulareLH,PL nodulare

Centro germinativo progressiCentro germinativo progressi--vamentevamente trasformato trasformato

Cellule Cellule ““poppop--corncorn”” o LPo LP

I centri germinativi progressivamente trasformatiI centri germinativi progressivamente trasformatipossono precedere od associarsi ad un LH,PLpossono precedere od associarsi ad un LH,PLnodulare; pur non essendo precursori morfologicinodulare; pur non essendo precursori morfologiciobbligati, vanno considerati come lesioni a obbligati, vanno considerati come lesioni a rischio.rischio.

Fan Z et al.: Fan Z et al.: Characterization of variant patterns of nodular lymphocyte predoCharacterization of variant patterns of nodular lymphocyte predominant minant Hodgkin lymphoma with Hodgkin lymphoma with immunohistologicimmunohistologic and clinical correlations.and clinical correlations.Am J Surg Pathol 2003; 27:1346Am J Surg Pathol 2003; 27:1346--5656..

•• Classic nodular pattern, BClassic nodular pattern, B--cellcell--richrich

•• Serpiginous/interconnected nodular patternSerpiginous/interconnected nodular pattern

•• Nodular with prominent extraNodular with prominent extra--nodular L&H cellsnodular L&H cells

•• Nodular with TNodular with T--cellcell--rich backgroundrich background

•• Diffuse pattern (TCRBCLDiffuse pattern (TCRBCL--like)like)

•• Diffuse, Diffuse, ““mothmoth--eateneaten”” with Bwith B--cellcell--rich backgroundrich background

CD30CD30 --/+ /+ ##

CD15CD15 --CD45CD45 ++EMAEMA + + CD20CD20 ++CD79aCD79a --/+/+JJ--chainchain +/+/--BclBcl--66 ++Oct.2, BOBOct.2, BOB--1 & PU.11 & PU.1 ++IRF4IRF4 ++d *d *

CD3CD3 --EBVEBV --p53p53 --

pabulum TIApabulum TIA--11++ bassobassopabulum CD57pabulum CD57++/PD1/PD1++ alto alto pabulum CD20pabulum CD20++ altoalto

CFDCFD ++## Roberts C et al. Histopathology 2002; 40:166Roberts C et al. Histopathology 2002; 40:166--70.70.* Carbone A et al. Br J * Carbone A et al. Br J HaematolHaematol 2002; 117:3662002; 117:366--72.72.

ImmunofenotipoImmunofenotipo ((UherovaUherova P et al. Am J Clin P et al. Am J Clin PatholPathol, 2003), 2003)

CD20CD20 CD3/CD57CD3/CD57CD79aCD79a

EMAEMA CD15CD15 CD30CD30

BclBcl--66 Oct2Oct2 CD21CD21

2020--25 September 2008, Bordeaux, France25 September 2008, Bordeaux, France

NLPHL with T/HRLBCLNLPHL with T/HRLBCL--like areaslike areasTypicalTypical areasareas of NLPHL of NLPHL withwith•• VaguelyVaguely nodular/diffusenodular/diffuse growth growth patternpattern•• Small B Small B cellscells in in backgroundbackground ((sometimessometimes

fewfew!)!)•• PD1 positive in PD1 positive in backgroundbackground ((rosettingrosetting))•• FDC meshworks in FDC meshworks in backgroundbackground +/+/--•• CD57 +/CD57 +/--T/HRLBCLT/HRLBCL--likelike areasareas (Progression?)(Progression?)•• ((VeryVery) ) smallsmall to to extendedextended, , nodularnodular oror diffuse diffuse

areasareas withwith total total lossloss of of smallsmall backgroundbackground B B cellscells (CD20 negative in (CD20 negative in thethe smallsmall cellscells!)!)

•• No FDC meshworks (CD21 negative!)No FDC meshworks (CD21 negative!)•• ScarceScarce to moderate CD57 to moderate CD57 and/orand/or PD1 PD1 cellscells

withoutwithout rosettingrosetting in in thesethese areasareas PD1PD1

PD1PD1

LSPLSP--11

LHPL LHPL –– CD20/LSP1CD20/LSP1

PU.1PU.1

IgDIgD

IgDIgD++, CD38, CD38++, IgM, IgM--, CD27, CD27--: : PrakashPrakash S et al. Am J S et al. Am J SurgSurg PatholPathol 30: 585, 30: 585, 20062006

LH di tipo classicoLH di tipo classico

•• 4 variet4 varietàà istologiche: istologiche: ricco in linfociti (RL)ricco in linfociti (RL)a sclerosi nodulare (SN)a sclerosi nodulare (SN)a cellularita cellularitàà mista (CM)mista (CM)a deplezione linfocitaria (DL)a deplezione linfocitaria (DL)

•• Distribuzione per fasce di etDistribuzione per fasce di etàà: bimodale (picchi nella : bimodale (picchi nella II/III e VI/VII decade di vita)II/III e VI/VII decade di vita)

•• Diffusione ordinata e progressiva (concetto su cui si Diffusione ordinata e progressiva (concetto su cui si basa lbasa l’’attuale sistema di stadiazione)attuale sistema di stadiazione)

•• Connessioni patogenetiche con lo EBVConnessioni patogenetiche con lo EBV

Overall survivalOverall survival EventEvent--free survivalfree survival

LH ricco in linfocitiLH ricco in linfociti

•• Un tempo, incluso nella Un tempo, incluso nella prevalenza linfocitaria.prevalenza linfocitaria.

•• Differisce dalla LHDifferisce dalla LH--PL PL per i seguenti motivi:per i seguenti motivi:-- le cellule neoplastiche le cellule neoplastiche non hanno carattere non hanno carattere poppop--corn,corn,-- le cellule diagnostiche le cellule diagnostiche non sono eccezionali,non sono eccezionali,-- ll’’assetto molecolare assetto molecolare èèquello del LH comune.quello del LH comune.

CD30CD30

CD15CD15

LH a sclerosi nodulareLH a sclerosi nodulare

•• VarietVarietàà pipiùù frequente in Italia e negli USA frequente in Italia e negli USA (l(l’’incidenza varia, tuttavia, in base allincidenza varia, tuttavia, in base all’’area area geografica).geografica).

•• Predilige i soggetti giovani di sesso femminile.Predilige i soggetti giovani di sesso femminile.•• Interessa spesso il mediastino anteriore (con Interessa spesso il mediastino anteriore (con

massa massa bulkybulky).).•• Integrazione dello EBV nel 25Integrazione dello EBV nel 25--30% dei casi.30% dei casi.

Sclerosi conSclerosi con

birifrangenzabirifrangenza

CellulaCellula

lacunarelacunare

Sclerosi Sclerosi nodulare di nodulare di

tipo IItipo II

•• Composizione dei noduli:Composizione dei noduli:

cellule neoplastiche + elementi reattivi; cellule neoplastiche + elementi reattivi; rapporto fra le due componenti variabile;rapporto fra le due componenti variabile;variabilitvariabilitàà della quota reattiva (linfociti, della quota reattiva (linfociti, plasmacellule, eosinofili, macrofagi e plasmacellule, eosinofili, macrofagi e fibroblasti); fibroblasti); possibili fenomeni di necrosi con palizzata.possibili fenomeni di necrosi con palizzata.

•• GradingGrading del LHdel LH--SNSN

SN di tipo I,SN di tipo I,SN di tipo IISN di tipo II; il termine si applica a casi ; il termine si applica a casi con:con:1. oltre l1. oltre l’’80% dei noduli con composizione 80% dei noduli con composizione fibrofibro--istiociticaistiocitica (tipo DL fibrosa),(tipo DL fibrosa),2. con oltre il 25% dei noduli costituiti da 2. con oltre il 25% dei noduli costituiti da blasti (d.d. con LGCA),blasti (d.d. con LGCA),

La SN2 sembra provvista di prognosi La SN2 sembra provvista di prognosi peggiore.peggiore.

von Wasielewsky S et al. Blood 2003; von Wasielewsky S et al. Blood 2003; 101:4063101:4063--9: eosinophilia, 9: eosinophilia, cellularcellular atypia atypia

and and lymphocytelymphocyte depletiondepletion..

CellularitCellularitàà mistamista

•• VarietVarietàà morfologiche:morfologiche:-- interfollicolare (d.d. con LCTP),interfollicolare (d.d. con LCTP),-- con ricca componente con ricca componente epitelioideepitelioide (idem).(idem).

FibrosaFibrosa

SarcomatosaSarcomatosa

LH a LH a deplezione deplezione linfocitarialinfocitaria

LH di tipo classico: fenotipoLH di tipo classico: fenotipoCD30CD30 + disomogeneo+ disomogeneoCD25, CD70, KiCD25, CD70, Ki--27, HLA27, HLA--DRDR ++CD15CD15 +/+/--CD45CD45 --EMAEMA eccezionaleeccezionaleFenotipo nullFenotipo null +/+/--CD20CD20 --/+/+CD79aCD79a raroraroJJ--chainchain --CD3CD3 raro (1raro (1--2%)2%)BSAP, IRF4BSAP, IRF4 ++Oct.2, BOBOct.2, BOB--1, PU.1 & Bcl1, PU.1 & Bcl--66 --proteina ALK/p80proteina ALK/p80 --FDCFDC +/+/--

CD30CD30 CD15CD15

CD30CD30

FarmacoFarmaco

CD30CD30AnticorpoAnticorpo

CD20CD20 CD3CD3

cHLcHLsubtypsubtypee

number of number of evaluable evaluable

casescases

CD30CD30positivepositiven %n %

CD79aCD79apositivepositiven %n %

NSNS 145145 141141 9797 102102 7070 4141 2828 1111 88

MCMC 8383 8383 100100 4848 5858 3535 4242 1414 1717

LRLR 1010 66 6060 44 4040 33 3030 11 1010

LDLD 55 55 100100 44 8080 11 2020 --

ncnc 1010 1010 100100 99 9090 44 4040 --

totaltotal 253253 245 245 (97%)(97%)

167 167 (66%)(66%)

84 84 (33%)(33%)

26 26 (10%)(10%)

Oct.2Oct.2 IRF4IRF4

BSAPBSAP

BB--CELL MATURATIONCELL MATURATION

EARLY BEARLY B--CELLSCELLS

PROPRO--BB PREPRE--BB

LATE LATE PREPRE--BB

MANTLEMANTLEBB--CELLSCELLS

CBCB CcCc PLASMABLASTSPLASMABLASTS PLASMA PLASMA CELLCELL

MATURE BMATURE B--CELLSCELLS SECRETORYSECRETORYBB--CELLSCELLS

PAX 5PAX 5

CD79aCD79a

CD20CD20

TPD52TPD52

CD30CD30

CD15CD15

CD45CD45

BSAP/PAXBSAP/PAX--55

TorlakovicTorlakovic E et al. Am J Surg Pathol 2002; 26:1343E et al. Am J Surg Pathol 2002; 26:1343--50.50.

LH di tipo classico: fenotipoLH di tipo classico: fenotipoCD30CD30 + disomogeneo+ disomogeneoCD25, CD70, KiCD25, CD70, Ki--27, HLA27, HLA--DRDR ++CD15CD15 +/+/--CD45CD45 --EMAEMA eccezionaleeccezionaleFenotipo nullFenotipo null +/+/--CD20CD20 --/+/+CD79aCD79a raroraroJJ--chainchain --CD3CD3 raro (1raro (1--2%)2%)BSAPBSAP, IRF4, IRF4 ++Oct.2, BOBOct.2, BOB--1, PU.11, PU.1 & Bcl& Bcl--66 --proteina ALK/p80proteina ALK/p80 --FDCFDC +/+/--

mutazioni mutazioni somatichesomatiche

proliferazioneproliferazione

selezione per selezione per affinitaffinitàà

ongoing ongoing mutationsmutations

CFDCFDAgAg

Genotipo:Genotipo:

Derivazione da elementi del centro germinativo, come dimostrato Derivazione da elementi del centro germinativo, come dimostrato dalldall’’esistenza di esistenza di mutazioni somatiche di IgVH.mutazioni somatiche di IgVH.

Deregulation of genes controlling the Deregulation of genes controlling the cell cycle and signaling pathways.cell cycle and signaling pathways.

Loss of the BLoss of the B--cell program.cell program.

GOHD:GOHD: genes involved in apoptosis genes involved in apoptosis and signaling (cytokines and signaling (cytokines included).included).

BOHD:BOHD: genes involved in fibroblastic genes involved in fibroblastic activation, angioactivation, angio--genesis, matrix genesis, matrix remodeling, proliferation and remodeling, proliferation and oncoonco--suppressor gene silencing.suppressor gene silencing.

CHL: genotyping on cell lines CHL: genotyping on cell lines

HinzHinz M et al. J Exp Med 2002; 196:605M et al. J Exp Med 2002; 196:605--17; 17; SchweingSchweing I et al. Blood 2003; I et al. Blood 2003; 101:1505101:1505--12; 12; DevillardDevillard E et al. Oncogene 2002; 21:3095E et al. Oncogene 2002; 21:3095--102. 102.

Gene expression profile of HodgkinGene expression profile of Hodgkin’’s Lymphoma cell lines:s Lymphoma cell lines:Inactivation of BInactivation of B--cell receptor signalling and Bcell receptor signalling and B--cell differentiation programcell differentiation program

BCL6BCL6

IRF4IRF4

BB--CELL RECEPTORCELL RECEPTOR

CD19CD19

CD20CD20

CD22CD22

CD79ACD79ACD79BCD79B

BRDG1BRDG1

HCLS1HCLS1

TNFRSF17TNFRSF17(B(B--cellcell maturationmaturation factor)factor)

LYNLYN

SYKSYK

VAVVAV

BTKBTK

Marafioti T et al.:Marafioti T et al.:

Intracellular signalling molecule Intracellular signalling molecule expression in Hodgkinexpression in Hodgkin’’s lymphoma.s lymphoma.

Blood 2004, 103: 188.Blood 2004, 103: 188.

Published data: Ig, JPublished data: Ig, J--chainchain NegNeg PosPos

CD20, CD79aCD20, CD79a Usually Usually negneg PosPos

CD15, CD30CD15, CD30 PosPos NegNeg

CD45CD45 NegNeg PosPos

BclBcl--66 NegNeg/Pos/Pos PosPos

EMAEMA NegNeg PosPos

OctOct--11 Pos/Pos/NegNeg PosPos

OctOct--2, BOB.12, BOB.1 NegNeg/Pos/Pos PosPos

PU.1PU.1 NegNeg PosPos

BSAPBSAP PosPos PosPos

IRF4IRF4 PosPos NegNeg

Present study: LynPresent study: Lyn NegNeg (with rare exceptions)(with rare exceptions) Usually Usually NegNeg

FynFyn Pos/Pos/NegNeg PosPos

SykSyk NegNeg PosPos

BLNKBLNK NegNeg PosPos

PLCPLC--gamma2gamma2 NegNeg PosPos

Gene expression profiling data:Gene expression profiling data: Not availableNot available

IgIg--(Kappa)(Kappa) DownDown--regulatedregulated

CD20CD20 DownDown--regulatedregulated

LynLyn DownDown--regulatedregulated

SykSyk DownDown--regulatedregulated

BLNKBLNK DownDown--regulatedregulated

PLCPLC--gamma2gamma2 DownDown--regulatedregulated

Molecular dataMolecular data CHLCHL LPLP--HLHL

Classical Hodgkin Classical Hodgkin lymphomalymphoma

SykSyk BLNKBLNK

PLCPLC--gamma 2gamma 2

Blood 2008; 111:2825-2832

HH--RS RS cellscells::““zombiezombie””

B B cellscells

apoptosis

Plasma cell

centroblast NF-kB

fascin

C-JUNNotch-1

G1G1MM

SSRbRb

ProliferationProliferation

Cyclin A, B1Cyclin A, B1CDK1CDK1

p16p16INK4aINK4a

Cyclin D, CDK4/6Cyclin D, CDK4/6p14p14ARFARF

Hdm2Hdm2p53, p21p53, p21WAF1WAF1

SKP2, p27SKP2, p27KIP1KIP1

Cyclin E, CDK2Cyclin E, CDK2

NFNF--kappaBkappaBBcl6Bcl6Bcl2, BaxBcl2, Bax

ApoptosisApoptosisSTAT1STAT1STAT3STAT3

Cyclin E, Cyclin ACyclin E, Cyclin ACDK1CDK1

G1 phaseG1 phaseCell GrowthCell Growth

S phaseS phaseDNA ReplicationDNA Replication

G2 phaseG2 phaseDNA RepairDNA Repair

DNA ReplicationDNA Replication

M phaseM phaseCell DivisionCell Division

EBVEBV

Cell Cycle and Apoptosis RegulationCell Cycle and Apoptosis Regulation

NFNF--κκB B constitutionalconstitutional expressionexpression

ApoptosisApoptosis inhibitioninhibition

(STAT(STAT--5a, CD40, CD154, CD80, CD86, 5a, CD40, CD154, CD80, CD86, BclBcl--xLxL, CCK7, Cyclin D2, , CCK7, Cyclin D2, Notch1, cNotch1, c--FLIP, FLIP, JunBJunB, , cc--metmet, etc. , etc. activationactivation))

IkBIkB mutationsmutationscc--JunJun aberrantaberrant

expressionexpressionCD30 CD30 expressionexpression

TRAF TRAF proteinproteinaggregationaggregation

LMPLMP--1 &1 &CD25CD25

2p 2p gainsgains

•• Western Countries: 35% Western Countries: 35% and 90% of NS and CM and 90% of NS and CM cases, respectively.cases, respectively.

•• Monoclonal episome.Monoclonal episome.

•• Latency II phenotype: LMPLatency II phenotype: LMP--11++, EBNA2, EBNA2--, EBER1/2, EBER1/2++, , ZEBRAZEBRA-- ((++ 6%).6%).

EBV integrationEBV integration EBER 1/2EBER 1/2

LMPLMP--11

Nature. 2011 Mar 17;471(7338):377Nature. 2011 Mar 17;471(7338):377--81. 81. EpubEpub 2011 Mar 2.2011 Mar 2.

MHC class II MHC class II transactivatortransactivator CIITA is a recurrent gene fusion partner in lymphoid cancers.CIITA is a recurrent gene fusion partner in lymphoid cancers.

SteidlSteidl C, Shah SP, C, Shah SP, WoolcockWoolcock BW, BW, RuiRui L, Kawahara M, L, Kawahara M, FarinhaFarinha P, Johnson NA, Zhao Y, P, Johnson NA, Zhao Y, TeleniusTelenius A, A, NeriahNeriah SB, SB, McPherson A, McPherson A, MeissnerMeissner B, B, OkoyeOkoye UC, UC, DiepstraDiepstra A, van den Berg A, Sun M, Leung G, Jones SJ, Connors JM, A, van den Berg A, Sun M, Leung G, Jones SJ, Connors JM, Huntsman DG, Savage KJ, Huntsman DG, Savage KJ, RimszaRimsza LM, LM, HorsmanHorsman DE, DE, StaudtStaudt LM, LM, SteidlSteidl U, U, MarraMarra MA, MA, GascoyneGascoyne RD.RD.

SourceDepartmentSourceDepartment of Pathology and Laboratory Medicine, Centre for Lymphoid Canceof Pathology and Laboratory Medicine, Centre for Lymphoid Cancers and the Centre for rs and the Centre for Translational and Applied Genomics, Vancouver, British Columbia,Translational and Applied Genomics, Vancouver, British Columbia, V5Z4E6, Canada.V5Z4E6, Canada.

AbstractAbstract

Chromosomal translocations are critically involved in the molecuChromosomal translocations are critically involved in the molecular pathogenesis of Blar pathogenesis of B--cell lymphomas, and highly cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molerecurrent and specific rearrangements have defined distinct molecular subtypes linked to unique cular subtypes linked to unique clinicopathologicalclinicopathological features. In contrast, several wellfeatures. In contrast, several well--characterized lymphoma entities still lack diseasecharacterized lymphoma entities still lack disease--defining defining translocation events. To identify novel fusion transcripts resultranslocation events. To identify novel fusion transcripts resulting from translocations, we investigated two ting from translocations, we investigated two Hodgkin lymphoma cell lines by Hodgkin lymphoma cell lines by wholewhole--transcriptome pairedtranscriptome paired--end sequencing (RNAend sequencing (RNA--seqseq)). Here we show a highly . Here we show a highly expressed expressed gene fusion involving the major histocompatibility complex (MHC)gene fusion involving the major histocompatibility complex (MHC) class II class II transactivatortransactivator CIITACIITA(MHC2TA) in KM(MHC2TA) in KM--H2 cells. In a subsequent evaluation of 263 BH2 cells. In a subsequent evaluation of 263 B--cell lymphomas, we also demonstrate that genomic cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal BCIITA breaks are highly recurrent in primary mediastinal B--cell lymphoma (38%) and classical Hodgkin lymphoma cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%)(cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of va. Furthermore, we find that CIITA is a promiscuous partner of various inrious in--frame gene fusions, and we frame gene fusions, and we report that CIITA gene alterations impact survival in primary mereport that CIITA gene alterations impact survival in primary mediastinal Bdiastinal B--cell lymphoma (PMBCL). As functional cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify consequences of CIITA gene fusions, we identify downregulationdownregulation of surface HLA class II expression and of surface HLA class II expression and overexpressionoverexpression of ligands of the receptor molecule programmed cell death 1 (CDof ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These 274/PDL1 and CD273/PDL2). These receptorreceptor--ligand interactions have been shown to impact antiligand interactions have been shown to impact anti--tumour immune responses in several cancers, tumour immune responses in several cancers, whereas decreased MHC class II expression has been linked to redwhereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity. Thus, our uced tumour cell immunogenicity. Thus, our findings suggest that recurrent rearrangements of CIITA may reprfindings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying esent a novel genetic mechanism underlying tumourtumour--microenvironment interactions across a spectrum of lymphoid cancmicroenvironment interactions across a spectrum of lymphoid cancers.ers.

CIITACIITA––BX648577BX648577 gene gene fusion observed using fusion observed using pairedpaired--end massively end massively parallel whole parallel whole transcriptome transcriptome sequencing.sequencing.

Molecular characterization Molecular characterization of the gene fusion of the gene fusion CIITACIITA––BX648577BX648577 in Hodgkin in Hodgkin lymphoma cell line KMlymphoma cell line KM--H2.H2.

FISH on tissue microarrays FISH on tissue microarrays showing recurrent showing recurrent CIITACIITA breakbreak--apart in cHL and PMBCL.apart in cHL and PMBCL.

linfoma di hodgkin - unibo.itcampus.unibo.it/81112/49/07a_lh.pdf · linfoma di hodgkin. thomas...

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