• No results found

Clinicopathologic and genetic features of primary cutaneous B-cell lymphoma

N/A
N/A
Protected

Academic year: 2021

Share "Clinicopathologic and genetic features of primary cutaneous B-cell lymphoma"

Copied!
14
0
0

Bezig met laden.... (Bekijk nu de volledige tekst)

Hele tekst

(1)

Clinicopathologic and genetic features of primary cutaneous B-cell

lymphoma

Hoefnagel, J.J.

Citation

Hoefnagel, J. J. (2007, January 11). Clinicopathologic and genetic features of primary

cutaneous B-cell lymphoma. Retrieved from https://hdl.handle.net/1887/8769

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the

Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/8769

Note: To cite this publication please use the final published version (if applicable).

(2)

CHAPTER 8

Summary and Discussion

(3)
(4)

8QWLO UHFHQWO\ SULPDU\ FXWDQHRXV %FHOO O\PSKRPD

&%&/ ZHUHFODVVLÀHGDFFRUGLQJWRHLWKHUWKH(XURSHDQ

2UJDQL]DWLRQ IRU 5HVHDUFK DQG 7UHDWPHQW RI &DQFHU

(257& FODVVLÀFDWLRQRUWKH:RUOG+HDOWK2UJDQL]DWLRQ

:+2  FODVVLÀFDWLRQ ,Q WKH SDVW \HDUV GLVFUHSDQFLHV

LQ WHUPLQRORJ\ DQG GHÀQLWLRQ RI WKH GLIIHUHQW W\SHV RI

&%&/ EHWZHHQ WKHVH WZR FODVVLÀFDWLRQ VFKHPHV KDYH

EHHQLQWHQVLYHO\GHEDWHG7KHVHGLVFUHSDQWSRLQWVRIYLHZ

GLG QRW RQO\ EULQJ XS D VHPDQWLF GLVFXVVLRQ EXW ZHUH

DOVR RI PDMRU FOLQLFDO LPSRUWDQFH ,Q IDFW LW FRQFHUQHG

FODVVLÀFDWLRQ RI &%&/ W\SHV LQ GLIIHUHQW GLDJQRVWLF

FDWHJRULHV ZLWK HLWKHU DQ LQGROHQW RU D PRUH DJJUHVVLYH

FOLQLFDO FRXUVH DQG FRQVHTXHQWO\ D FKRLFH EHWZHHQ

DJJUHVVLYHDQGQRQDJJUHVVLYHPRGHVRIWUHDWPHQW

 7KH VWXGLHV SUHVHQWHG LQ WKLV WKHVLV LQYHVWLJDWHG

FOLQLFRSDWKRORJLF DQG PROHFXODU JHQHWLF IHDWXUHV RI WKH

WKUHH PDLQ W\SHV RI &%&/ UHFRJQL]HG LQ WKH (257&

FODVVLÀFDWLRQ SULPDU\ FXWDQHRXV LPPXQRF\WRPD 

SULPDU\ FXWDQHRXV PDUJLQDO ]RQH %FHOO O\PSKRPD

3&,3&0=/  SULPDU\ FXWDQHRXV IROOLFOH FHQWHU FHOO

O\PSKRPD 3&)&&/  DQG SULPDU\ FXWDQHRXV ODUJH %

FHOO O\PSKRPD RI WKH OHJ 3&/%&/OHJ  7KH DLPV RI

WKHVHVWXGLHVZHUH  WRGHÀQHPRUHFOHDUO\WKHGLIIHUHQW

W\SHV RI &%&/   WR LGHQWLI\ QRYHO GLDJQRVWLF DQG

SURJQRVWLFPDUNHUVDQG  WRJDLQDEHWWHUXQGHUVWDQGLQJ

RIWKHPROHFXODUPHFKDQLVPVXQGHUO\LQJWKHSDWKRJHQHVLV

RI WKHVH O\PSKRPDV 7KH VWXGLHV UHVXOWHG LQ WKH

LGHQWLÀFDWLRQRIQHZPDUNHUVIDFLOLWDWLQJWKHGLIIHUHQWLDO

GLDJQRVLVEHWZHHQ3&)&&/DQG3&0=/RQWKHRQHKDQG

DQG EHWZHHQ 3&)&&/ DQG 3&/%&/OHJ RQ WKH RWKHU

SURYLGHGDGGLWLRQDOVXSSRUWIRUWKHJHUPLQDOFHQWHURULJLQ

RIWKHWXPRUFHOOVRI3&)&&/DQGVKRZHGWKDW3&)&&/

ZLWK D GLIIXVH ODUJH FHOO KLVWRORJ\ DQG 3&/%&/OHJ DUH

FOHDUO\GLVWLQFWGLVHDVHHQWLWLHV

 $OWRJHWKHU WKHVH REVHUYDWLRQV KDYH OHG WR D EHWWHU

GHÀQLWLRQRIWKHGLIIHUHQWW\SHVRI&%&/DQGKDYHEHHQ

LPSRUWDQW LQ GLVFXVVLRQV EHWZHHQ UHSUHVHQWDWLYHV RI

WKH (257& DQG :+2 FODVVLÀFDWLRQ VFKHPHV ZKLFK

XOWLPDWHO\ OHG WR WKH GHYHORSPHQW RI D QHZ FRQVHQVXV

FODVVLÀFDWLRQIRUSULPDU\FXWDQHRXVO\PSKRPD VHH7DEOH

  ,Q WKLV :+2(257& FODVVLÀFDWLRQ WKH IROORZLQJ

WKUHH PDLQ W\SHV RI &%&/ DUH UHFRJQL]HG SULPDU\

FXWDQHRXV PDUJLQDO ]RQH %FHOO O\PSKRPD 3&0=/ 

SULPDU\ FXWDQHRXV IROOLFOH FHQWHU O\PSKRPD 3&)&/  DQG SULPDU\ FXWDQHRXV ODUJH %FHOO O\PSKRPD OHJ W\SH

3&/%&/OHJW\SH $GGLWLRQDOO\DFDWHJRU\RISULPDU\

FXWDQHRXVODUJH%FHOOO\PSKRPDRWKHU 3&/%&/RWKHU  ZDVLQFOXGHG

 ,QWKLVÀQDOFKDSWHUWKHPDLQIHDWXUHVRIWKHWKUHHW\SHV

RI&%&/ZLOOEHGHVFULEHGDQGLWZLOOEHLQGLFDWHGKRZ

WKHVWXGLHVLQFOXGHGLQWKLVWKHVLVDQGRWKHUVWXGLHVKDYH

FRQWULEXWHG WR WKH QHZ :+2(257& FODVVLÀFDWLRQ



7DEOH&ODVVLÀFDWLRQ RI SULPDU\ FXWDQHRXV %FHOO O\PSKRPD DFFRUGLQJ WR WKH (XURSHDQ 2UJDQL]DWLRQ IRU

5HVHDUFK DQG7UHDWPHQW RI &DQFHU (257&  FODVVLÀFDWLRQ WKH:RUOG +HDOWK 2UJDQL]DWLRQ :+2  FODVVLÀFDWLRQDQGWKH:+2(257&FODVVLÀFDWLRQ

(257&FODVVLÀFDWLRQ :+2FODVVLÀFDWLRQ :+2(257&FODVVLÀFDWLRQ

3ULPDU\FXWDQHRXVLPPXQRF\WRPD

PDUJLQDO]RQH%FHOOO\PSKRPD

([WUDQRGDOPDUJLQDO]RQH%FHOOO\PSKRPD

RIPXFRVDDVVRFLDWHGO\PSKRLGWLVVXH

0$/7O\PSKRPD

3ULPDU\FXWDQHRXVPDUJLQDO]RQH%FHOO

O\PSKRPD

3ULPDU\FXWDQHRXVIROOLFOHFHQWHUFHOO

O\PSKRPD

&XWDQHRXVIROOLFOHFHQWHUO\PSKRPD 'LIIXVHODUJH%FHOOO\PSKRPD‚

3ULPDU\FXWDQHRXVIROOLFOHFHQWHU

O\PSKRPD

3ULPDU\FXWDQHRXVODUJH%FHOO

O\PSKRPDRIWKHOHJ

'LIIXVHODUJH%FHOOO\PSKRPD 3ULPDU\FXWDQHRXVODUJH%FHOO

O\PSKRPDOHJW\SH

3ODVPDF\WRPD 3ODVPDF\WRPD

,QWUDYDVFXODUODUJH%FHOOO\PSKRPD 'LIIXVHODUJH%FHOOO\PSKRPD

LQWUDYDVFXODU

3ULPDU\FXWDQHRXVODUJH%FHOO

O\PSKRPDRWKHU

Â&DVHVZLWKD SDUWO\ IROOLFXODUJURZWKSDWWHUQ

‚&DVHVZLWKDGLIIXVHLQÀOWUDWHRIODUJHQHRSODVWLF%FHOOV

(5)



)RU HDFK W\SH GHÀQLWLRQ DQG WHUPLQRORJ\ DQG FOLQLFR

SDWKRORJLF DQG PROHFXODU JHQHWLF IHDWXUHV ZLOO EH

GLVFXVVHG,QDGGLWLRQLVVXHVIRUIXWXUHUHVHDUFKZLOOEH

LQGLFDWHG

1. Primary cutaneous marginal zone B-cell lymphoma

'HÀQLWLRQDQGWHUPLQRORJ\

3&0=/DUHLQGROHQW&%&/FKDUDFWHUL]HGE\DSUROLIHUDWLRQ

RI VPDOO O\PSKRLG %FHOOV LQFOXGLQJ PDUJLQDO ]RQH

FHQWURF\WHOLNH  FHOOV O\PSKRSODVPDF\WRLG FHOOV DQG

SODVPDFHOOV,QWKH(257&FODVVLÀFDWLRQWKHWHUP3&,

3&0=/ZDVXVHGWRLQGLFDWHWKDW3&0=/ZDVWKHQHZ

QDPHIRUFDVHVGHVLJQDWHGSUHYLRXVO\DVLPPXQRF\WRPDV

DFFRUGLQJ WR WKH FULWHULD RI WKH .LHO FODVVLÀFDWLRQ4The PDLQUHDVRQWRSUHIHUWKHWHUP3&,ZDVWKDWDWWKHWLPH

WKH (257& FODVVLÀFDWLRQ ZDV IRUPXODWHG WKH WHUP

3&0=/ZDVVWLOOLOOGHÀQHGDQGXVHGLQGLIIHUHQWZD\V

6RPHUHSRUWVHYHQVXJJHVWHGWKDWQRWRQO\3&,EXWDOVR

PRVW3&)&&/ZHUHGHULYHGIURPPDUJLQDO]RQH%FHOOV

DQGVKRXOGEHFODVVLÀHGDFFRUGLQJO\7KHPDLQSUREOHP

ZDVWKDWPDUNHUVWRGLIIHUHQWLDWHEHWZHHQIROOLFOHFHQWHU

FHOOVDQGPDUJLQDO]RQH%FHOOVZHUHQRWDYDLODEOHDWWKDW

WLPH

 7KH UHVXOWV RI WKH LPPXQRKLVWRFKHPLFDO VWXG\

SUHVHQWHG LQ chapter 2 VKRZHG GLVWLQFWLYH H[SUHVVLRQ

SDWWHUQV IRU WKH DQWLDSRSWRWLF SURWHLQ %FO DQG WKH

JHUPLQDOFHQWHUPDUNHUV%FODQG&'LQ3&0=/DQG

3&)&&/UHVSHFWLYHO\ VHH7DEOH 7KHWXPRUFHOOVRI

3&)&&/ FRQVLVWHQWO\ H[SUHVVHG %FO DQG UDUHO\ %FO

DQG&'ZKHUHDVWKHWXPRUFHOOVRI3&0=/XQLIRUPO\

VKRZHG %FO H[SUHVVLRQ ZLWK DEVHQFH RI %FO DQG

&'H[SUHVVLRQ7KHVHGLVWLQFWLYH%FO%FOVWDLQLQJ

SDWWHUQVIDFLOLWDWHWKHGLIIHUHQWLDOGLDJQRVLVEHWZHHQERWK

HQWLWLHVDQGDOORZLQFRPELQDWLRQZLWKPRUSKRORJLFDQG

RWKHU LPPXQRSKHQRW\SLF IHDWXUHV GLVWLQFWLRQ EHWZHHQ

3&0=/DQG3&)&&/LQDOPRVWDOOFDVHV7KHFRQVLVWHQW

UHVXOWVRIWKLVVWXG\DQGVLPLODUÀQGLQJVE\RWKHUVLQGLFDWH

WKDWE\XVLQJWKH%FO%FOSKHQRW\SHDVDQDGGLWLRQDO

GLDJQRVWLF FULWHULRQ LW LV LPSURSDEOH WKDW 3&)&&/ DUH

LQFRUUHFWO\ GLDJQRVHG DV 3&0=/ ,Q DGGLWLRQ WKH WHUP

LPPXQRF\WRPDKDVEHFRPHFRQIXVLQJVLQFHLQWKH:+2

FODVVLÀFDWLRQWKLVWHUPUHIHUVWRDUDUHJURXSRIV\VWHPLF

O\PSKRSODVPDF\WLFO\PSKRPDVJHQHUDOO\DVVRFLDWHGZLWK

:DOGHQVWU|PVPDFURJOREXOLQDHPLD)RUWKHVHUHDVRQVWKH

WHUP3&0=/LVFXUUHQWO\DFFHSWHGDVWKHPRVWDSSURSLDWH

WHUPIRUWKLVW\SHRI&%&/DQGKDVEHHQDGRSWHGE\WKH

UHFHQW :+2(257& FODVVLÀFDWLRQ ,Q DGGLWLRQ UDUH

FDVHVRISULPDU\FXWDQHRXVSODVPDF\WRPDDUHLQFOXGHGLQ

WKLVFDWHJRU\EHFDXVHWKH\VKRZFRQVLGHUDEOHRYHUODSSLQJ

FOLQLFRSDWKRORJLFIHDWXUHVZLWK3&0=/

1.2. Clinicopathologic features

%DVHGRQQHZGLDJQRVWLFFULWHULDFOLQLFDODQGWKHUDSHXWLF

FKDUDFWHULVWLFV RI  3&0=/ SDWLHQWV ZHUH UHYLHZHG

DQGSUHVHQWHGLQchapter 38&OLQLFDOO\3&0=/XVXDOO\

SUHVHQW ZLWK HU\WKHPDWRXV RU VNLQFRORUHG SDSXOHV

7DEOH,PPXQRKLVWRFKHPLFDOH[SUHVVLRQRI%FO%FO&'0XP,5)DQG)2;3LQFXWDQHRXV%FHOO

O\PSKRSUROLIHUDWLYHGLVRUGHUVLQFOXGLQJSVHXGR%FHOOO\PSKRPDSULPDU\FXWDQHRXVPDUJLQDO]RQH%

FHOOO\PSKRPD 3&0=/ SULPDU\FXWDQHRXVIROOLFOHFHQWHUO\PSKRPD 3&)&/ VHFRQGDU\FXWDQHRXV

IROOLFXODUO\PSKRPD VHFRQGDU\)/ DQGSULPDU\FXWDQHRXVODUJH%FHOOO\PSKRPDOHJW\SH 3&/%&/

leg type).

Bcl-2 Bcl-6 &' Mum1/IRF4 )2;3

pseudo B-cell lymphoma*     

PCMZL     

PCFCL     

secondary FL     

3&/%&/OHJW\SH     

Abbreviations: JHUPLQDOFHQWHUFHOOV

(6)



SODTXHV QRGXOHV RU WXPRUV SUHIHUHQWLDOO\ ORFDOL]HG RQ

WKH WUXQN RU WKH H[WUHPLWLHV EXW UDUHO\ LQ WKH KHDG DQG

QHFN UHJLRQ ,Q FRQWUDVW WR SUHYLRXV VWXGLHV FOLQLFDO

SUHVHQWDWLRQZLWKPXOWLIRFDOVNLQOHVLRQVZDVREVHUYHGLQ

WKHPDMRULW\RISDWLHQWV  $SSUR[LPDWHO\KDOIRI

WKHSDWLHQWVVWXGLHGGHYHORSHGFXWDQHRXVUHODSVLQJGLVHDVH

LQSDUWLFXODULQFDVHVLQLWLDOO\SUHVHQWLQJZLWKPXOWLIRFDO

VNLQOHVLRQVEXWH[WUDFXWDQHRXVGLVVHPLQDWLRQZDVUDUHO\

REVHUYHG &RQVLVWHQW ZLWK LQLWLDO VWXGLHV WKH UHVXOWV RI

WKLV VWXG\ FRQÀUP WKH LQGROHQW FOLQLFDO EHKDYLRXU DQG

H[FHOOHQWSURJQRVLVRI3&0=/ZLWKD\HDUVXUYLYDOFORVH

WR $Q DVVRFLDWLRQ ZLWK D Borrelia burgdorferi LQIHFWLRQ KDV EHHQ UHSRUWHG LQ D VLJQLÀFDQW PLQRULW\ RI

3&0=/ FDVHV IURP (XURSHDQ FRXQWULHV ZLWK HQGHPLF

Borrelia burgdorferi LQIHFWLRQVEXWQRWLQDODUJHQXPEHU

RI$PHULFDQDQG$VLDQFDVHV7KLVGLIIHUHQFHPLJKWEH

H[SODLQHGE\GLIIHUHQWVHURW\SHVRIBorrelia burgdorferi HQGHPLFLQWKH86$DQG(XURSHUHVSHFWLYHO\

 +LVWRSDWKRORJLFDOO\ 3&0=/ VKRZ SDWFK\ WR

GLIIXVH LQÀOWUDWHV FRPSRVHG RI VPDOO O\PSKRF\WHV

LQFOXGLQJ PDUJLQDO ]RQH FHQWURF\WHOLNH  %FHOOV

O\PSKRSODVPDF\WRLG FHOOV DQG SODVPD FHOOV VKRZLQJ

PRQRW\SLFLQWUDF\WRSODVPLFLPPXQRJOREXOLQOLJKWFKDLQ

H[SUHVVLRQ 7KH PDUJLQDO ]RQH %FHOOV H[SUHVV &'

&'D DQG %FO EXW DUH QHJDWLYH IRU &' &' DQG

%FO ([SUHVVLRQ RI )2;3 PD\ EH REVHUYHG LQ VRPH

FDVHV (chapter 7) 3ODVPD FHOOV VKRZ H[SUHVVLRQ RI

&'D &' 0XP,5) DQG %OLPS 5HDFWLYH

JHUPLQDO FHQWHUV VKRZ W\SLFDO H[SUHVVLRQ RI %FO DQG

&'EXWDUHQHJDWLYHIRU%FO

 7KH UHVXOWV RI WKH VWXG\ SUHVHQWHG LQ chapter 3 VKRZHGWKDWSDWLHQWVLQLWLDOO\SUHVHQWLQJZLWKVROLWDU\RU

ORFDOL]HG VNLQ OHVLRQV FDQ EH VXFFHVVIXOO\ WUHDWHG ZLWK

HLWKHU UDGLRWKHUDS\ RU VXUJLFDO H[FLVLRQ8 ,Q FDVHV ZLWK

DQ DVVRFLDWHG Borrelia burgdorferi LQIHFWLRQ V\VWHPLF

DQWLELRWLFV VKRXOG EH WULHG ÀUVW )RU SDWLHQWV SUHVHQWLQJ

ZLWKPXOWLIRFDOVNLQOHVLRQVWUHDWPHQWZLWKFKORUDPEXFLO

UHVXOWHGLQDFRPSOHWHUHPLVVLRQLQPRUHWKDQRIWKH

FDVHV $OWHUQDWLYHO\ VHYHUDO VWXGLHV UHSRUWHG EHQHÀFLDO

HIIHFWV RI WUHDWPHQW ZLWK LQWUDOHVLRQDO ULWX[LPDE DQWL

&' DQWLERG\  RU LQWHUIHURQ DOSKD LQ SDWLHQWV ZLWK

H[WHQVLYH VNLQ OHVLRQV +RZHYHU WKH QXPEHU RI

SDWLHQWVLQFOXGHGLQWKHVHVWXGLHVLVVWLOOOLPLWHG,QFDVHRI

FXWDQHRXVUHODSVHWUHDWPHQWLVDLPHGDWSDOOLDWLRQUDWKHU

WKDQ FXUH DQG WKHUDSHXWLF HIIHFWV VKRXOG EH FDUHIXOO\

ZHLJKWHGDJDLQVWWKHSRWHQWLDOVLGHHIIHFWV,QPDQ\SDWLHQWV

DZDLWDQGVHHSROLF\FDQEHIROORZHGEXWLQGLYLGXDOVNLQ

OHVLRQVFDQEHWUHDWHGHLWKHUZLWKWRSLFDORULQWUDOHVLRQDO

VWHURLGVRUORZGRVHUDGLRWKHUDS\LIUHTXLUHG

7DEOH$QDWRPLF VLWH LQIHFWLRXV DJHQWV DQG FKURPRVRPDO WUDQVORFDWLRQV LQ PXFRVDDVVRFLDWHG O\PSKRLG WLVVXH 0$/7  lymphomas.

Anatomic site Infectious agent Chromosomal

Translocation Frequency (%)

Stomach Helicobacter pylori W  TT

W  ST





Lung ? W  TT

W  ST





Intestine Campylobacter jejuni W  TT

W  ST





2FXODUDGQH[D Chlamydia psittaci W  ST

W  TT





Skin Borrelia burgdorferi W  TT

W  ST





Salivary gland "DXWRLPPXQH W  TT 

Thyroid "DXWRLPPXQH W  ST 

(7)



1.3. Genetic features

3&0=/ DUH SDUW RI WKH EURDGHU JURXS RI H[WUDQRGDO

PDUJLQDO ]RQH %FHOO O\PSKRPDV RI 0$/7 H[WUDQRGDO

0=/  7KHVH O\PSKRPDV PD\ GHYHORS LQ D QXPEHU RI

DQDWRPLF VLWHV LQFOXGLQJ WKH VWRPDFK VPDOO LQWHVWLQH

VDOLYDU\ JODQG OXQJ WK\URLG RFXODU DGQH[D DQG WKH

VNLQ 'HVSLWH RFFXUUHQFH LQ YDULRXV H[WUDQRGDO VLWHV

WKHVH O\PSKRPDV VKDUH D QXPEHU RI FRPPRQ IHDWXUHV

WKH PRVW VWULNLQJ EHLQJ WKHLU SRVVLEOH DVVRFLDWLRQ

ZLWK FKURQLF LQIHFWLRQV VXFK DV Helicobacter pylori

DVVRFLDWHG JDVWULWLV RU DXWRLPPXQH GLVHDVHV These FRQGLWLRQV WULJJHU D SHUVLVWHQW O\PSKRF\WH SUROLIHUDWLRQ

FRQVWLWXWLQJ DQ LQFUHDVHG ULVN IRU WKH RFFXUUHQFH RI

DGGLWLRQDO WUDQVIRUPLQJ RQFRJHQHWLF HYHQWV JLYLQJ ULVH

WRO\PSKRPD$IWHUHelicobacter pylori ZDVLGHQWLÀHG

DV DFDXVDWLYHDJHQWLQJDVWULF0$/7O\PSKRPDVHYHUDO

RWKHU LQIHFWLRXV DVVRFLDWLRQV KDYH EHHQ UHSRUWHG IRU

Borrelia burgdorferi VNLQ  Chlamydia psittaci RFXODU

DGQH[DH  Campylobacter jejuni LQWHVWLQH  DQG KHSDWLWLV

& YLUXV VSOHHQ  VHH 7DEOH   6HYHUDO VPDOO VWXGLHV

VKRZ HYLGHQFH RI RQJRLQJ PXWDWLRQV LQ 3&0=/ IXUWKHU

VXSSRUWLQJDQWLJHQGULYHQFORQDOH[SDQVLRQRIWKHWXPRU

FHOOV

 5HFHQWO\ IRXU PDLQ UHFXUUHQW FKURPRVRPDO

WUDQVORFDWLRQV KDYH EHHQ LPSOLFDWHG LQ WKH SDWKRJHQHVLV

RI 0$/7 O\PSKRPD LQFOXGLQJ W  TT 

W  ST W  TT DQGW  ST 

 7KHVH WUDQVORFDWLRQV KDYH EHHQ H[FOXVLYHO\ IRXQG LQ

0$/7O\PSKRPDDQGWKHLUIUHTXHQF\YDULHVFRQVLGHUDEO\

DW GLIIHUHQW DQDWRPLF VLWHV 7DEOH   7KH RQFRJHQLF

DFWLYLW\RIWKHGLVSDUDWHWUDQVORFDWLRQVW  W  

DQG W   LV OLQNHG WR WKH VDPH VLJQDOLQJ SDWKZD\

UHVXOWLQJ LQ DQWLJHQ UHFHSWRUPHGLDWHG DFWLYDWLRQ RI 1)

K%7KHWHUP1)K% QXFOHDUIDFWRUK% UHIHUVWR

GLPHULFWUDQVFULSWLRQIDFWRUVEHORQJLQJWRWKH5(/IDPLO\

ZLWK D FHQWUDO UROH LQ DGDSWLYH LPPXQLW\ LQÁDPPDWLRQ

DQGWKHLQKLELWLRQRIDSRSWRVLV,Qchapter 4 WKHSUHVHQFH

RI D W   LQYROYLQJ IGH DQG MALT1 JHQHV ZDV

GHPRQVWUDWHGLQ3&0=/FDVHVDQGXQWLOSUHVHQWDWRWDO

QXPEHURI  FDVHVKDUERULQJWKLVWUDQVORFDWLRQ

KDVEHHQUHSRUWHG,QRQHRIWKH3&0=/FDVHVZLWKD

W  DFRQFXUUHQWWULVRP\ZDVGHPRQVWUDWHG:KROH

RUSDUWLDOWULVRP\KDVEHHQGHVFULEHGLQDERXWRI

0$/7 O\PSKRPDV 2WKHU WULVRPLHV LQFOXGLQJ WULVRPLHV

DQGDUHOHVVIUHTXHQWO\UHSRUWHG

 0RVW UHFHQWO\ WKH FKURPRVRPDO WUDQVORFDWLRQ W   LQYROYLQJFOXP1DQGIGHJHQHVKDVEHHQGHVFULEHGLQ

0$/7O\PSKRPDVLQYROYLQJWKHWK\URLGRFXODUDGQH[D

DQGDOVRLQWZRFDVHVRIWKHVNLQ7KLVWUDQVORFDWLRQEULQJV

the FOXP1JHQHXQGHUFRQWURORIWKHIGH JHQHHQKDQFHU

DQGGHUHJXODWHVLWVH[SUHVVLRQEXWWKHRQFRJHQLFUROHRI

WKLV WUDQVORFDWLRQ LV VWLOO XQFOHDU ,Q chapter 7 D W   FRXOG QRW EH GHPRQVWUDWHG LQ QLQH FDVHV RI 3&0=/

DOWKRXJK)2;3SURWHLQH[SUHVVLRQZDVSUHVHQWLQRI

FDVHV,WKDVEHHQUHSRUWHGWKDW)2;3RYHUH[SUHVVLRQLV

QRWRQO\REVHUYHGLQFDVHVZLWKWKHWUDQVORFDWLRQEXWDOVR

LQFDVHVZLWKDWULVRP\VXJJHVWLQJWKDWLQFUHDVHGJHQH

FRS\QXPEHUPD\EHDQRWKHUPHFKDQLVPRIGHUHJXODWHG

H[SUHVVLRQ

 7DNHQ WRJHWKHU WKH SUHVHQFH RI WZR RI WKH NQRZQ

0$/7O\PSKRPDVSHFLÀFWUDQVORFDWLRQVLQDSURSRUWLRQ

RI 3&0=/ DQG WKH FKURQLF DQWLJHQ VWLPXODWLRQ DV

FRPPRQ SDWKRJHQLF GHQRPLQDWRU DGG WR WKH HYLGHQFH

RI FORVH VLPLODULWLHV EHWZHHQ 3&0=/ DQG RWKHU 0$/7

O\PSKRPDV1HYHUWKHOHVVWKHVLWHVSHFLÀFLW\RIDVVRFLDWHG

LQIHFWLRQVDQGFKURPRVRPDOWUDQVORFDWLRQVHPSKDVL]HVWKH

VLJQLÀFDQFHRIDQDWRPLFORFDOL]DWLRQGHWHUPLQLQJXQLTXH

IHDWXUHVRIGLVWLQFW0$/7O\PSKRPDW\SHVLQFOXGLQJVLWH

UHODWHGFOLQLFDOEHKDYLRXUDQGWKHUDSHXWLFSRVVLELOLWLHV

2. Primary cutaneous follicle center lymphoma

'HÀQLWLRQDQGWHUPLQRORJ\

$V RXWOLQHG LQ FKDSWHU  WKH WHUP ¶SULPDU\ FXWDQHRXV

IROOLFOHFHQWHUFHOOO\PSKRPD·IRUPHGWKHPRVWLPSRUWDQW

FDXVHRIPLVXQGHUVWDQGLQJEHWZHHQWKH(257&DQG:+2

V\VWHPV UHJDUGLQJ WKH FODVVLÀFDWLRQ RI &%&/ ,Q WKH

(257&FODVVLÀFDWLRQ3&)&&/ZDVGHÀQHGDVDWXPRU

FRPSRVHG RI IROOLFOH FHQWHU FHOOV ZLWK HLWKHU D SDUWLDO  IROOLFXODU RU LQ WKH PDMRULW\ RI FDVHV D GLIIXVH JURZWK

SDWWHUQ &OLQLFDOO\ 3&)&&/ SUHVHQW FKDUDFWHULVWLFDOO\

ZLWKVROLWDU\RUJURXSHGVNLQOHVLRQVRQWKHKHDGRURQWKH

WUXQN DUH UHVSRQVLYH WR UDGLRWKHUDS\ DQG FKDUDFWHUL]HG

E\ DQ H[FHOOHQW SURJQRVLV +RZHYHU VLQFH WKHVH

O\PSKRPDV ODFNHG D IROOLFXODU JURZWK SDWWHUQ LQ PRVW

FDVHVDQGGLGQRWKDUERUPROHFXODUIHDWXUHVRIIROOLFXODU

O\PSKRPD )/  LH SUHVHQFH RI D W   DQG %FO

SURWHLQ H[SUHVVLRQ WKHLU SURSRVHG JHUPLQDO FHQWHU FHOO

RULJLQ ZDV TXHVWLRQHG ,Q WKH :+2 FODVVLÀFDWLRQ

WKLV JURXS RI &%&/ ZDV QRW UHFRJQL]HG DV D GLVWLQFW

HQWLW\EXWFDWHJRUL]HGHLWKHUDVDYDULDQWRI)/LQFDVHRI

D SDUWLDO IROOLFXODUJURZWKSDWWHUQ LHFXWDQHRXVIROOLFOH

FHQWHUO\PSKRPD RUDVDGLIIXVHODUJH%FHOOO\PSKRPD

LQFDVHRIDGLIIXVHJURZWKSDWWHUQZKLFKPD\UHVXOWLQ

RYHUWUHDWPHQWZLWKPXOWLDJHQWFKHPRWKHUDS\UDWKHUWKDQ

UDGLRWKHUDS\

 7R DGGUHVV WKLV LVVXH WKH LPPXQRKLVWRFKHPLFDO

H[SUHVVLRQRIDQWLDSRSWRWLFSURWHLQ%FODQGWKHJHUPLQDO

FHQWHU PDUNHUV %FO DQG &' PROHFXOHV QRUPDOO\

H[SUHVVHG E\ WKH WXPRU FHOOV RI )/ ZDV LQYHVWLJDWHG LQ

chapter 2 7KH UHVXOWV VKRZHG D FRQVLVWHQW H[SUHVVLRQ

RI %FO SURWHLQ LQ DOO 3&)&&/ FDVHV VXSSRUWLQJ WKHLU

GHULYDWLRQRIIROOLFOHFHQWHUFHOOVVLQFH%FOLVJHQHUDOO\

DFFHSWHGDVDPDUNHUIRUJHUPLQDOFHQWHU%FHOOV VHH7DEOH

 $GGLWLRQDOH[SUHVVLRQRI3D[382FWDQG%2%

(8)



EXWQRWRI%OLPSDQGQRWRUUDUHO\RI0XP,5)DQG

)2;3ZDVREVHUYHGLQWKHLPPXQRKLVWRFKHPLFDOVWXG\

described in chapter 7.7KHH[SUHVVLRQSDWWHUQRIWKHVH

PDUNHUVZDVVLPLODUWRWKDWREVHUYHGLQQRUPDOJHUPLQDO

FHQWHUFHOOVDQGWKXVLQOLQHZLWKWKHSRVWXODWHGGHULYDWLRQ

RI IROOLFOH FHQWHU FHOOV )XUWKHU HYLGHQFH IRU D JHUPLQDO

FHQWHU FHOO RI RULJLQ LV SURYLGHG E\ WKH GHPRQVWUDWLRQ

RI RQJRLQJ  VRPDWLF PXWDWLRQV LQ WKH YDULDEOH UHJLRQV

RI ,*+ JHQH RI WKHVH O\PSKRPDV )LQDOO\ LW ZDV

GHPRQVWUDWHGLQchapter 5WKDWWKHJHQHH[SUHVVLRQSURÀOH

RI 3&)&&/ VKRZHG VLPLODULWLHV WR WKH JHQH H[SUHVVLRQ

SURÀOHRIJHUPLQDOFHQWHU%FHOO *&% OLNHGLIIXVHODUJH

%FHOOO\PSKRPDV '/%&/ ZKHUHDVWKHJHQHH[SUHVVLRQ

SURÀOHRI3&/%&/OHJZDVPRUHVLPLODUWRDFWLYDWHG%

FHOO $%& OLNH'/%&/

 $W SUHVHQW WKHUH LV FRQVHQVXV WKDW 3&)&&/ IRUP D

VSHFWUXP RI GLVHDVH LQFOXGLQJ FDVHV ZLWK D IROOLFXODU

IROOLFXODUDQGGLIIXVHRUGLIIXVHJURZWKSDWWHUQVKRZLQJ

D SUHGRPLQDQFH RI JHQHUDOO\ PHGLXPVL]HG WR ODUJH

FHQWURF\WHVZLWKYDULDEOHQXPEHUVRIDGPL[HGFHQWUREODVWV

DQGLPPXQREODVWV,QWKH:+2(257&FODVVLÀFDWLRQWKLV

JURXSLVUHIHUUHGWRDV¶SULPDU\IROOLFOHFHQWHUO\PSKRPD·

3&)&/  +RZHYHU FRQVLVWHQW ZLWK WKH UHVXOWV RI D

UHFHQW ODUJH PXOWLFHQWHU VWXG\ LQ ZKLFK D URXQG FHOO

PRUSKRORJ\ZDVLGHQWLÀHGDVDQLQGHSHQGHQWSURJQRVWLF

IDFWRU LQ ERWK 3&)&&/ DQG 3&/%&/OHJ FDVHV ZLWK D

GLIIXVHSUROLIHUDWLRQRIFHQWUREODVWVDQGRULPPXQREODVWV

ORFDOL]HGRQWKHKHDGRUWUXQNDUHQRORQJHUFODVVLÀHGDVD

3&)&/EXWDVSULPDU\FXWDQHRXVODUJH%FHOOO\PSKRPD

OHJ W\SH 3&/%&/ OHJ W\SH 48 ,Q RWKHU ZRUGV D PDMRU

GLIIHUHQFH ZLWK WKH SUHYLRXV (257& FODVVLÀFDWLRQ LV

WKDW &%&/ ZLWK D GLIIXVH JURZWK SDWWHUQ DUH FODVVLÀHG

SULPDULO\RQWKHEDVLVRIPRUSKRORJ\LQVWHDGRIDQDWRPLF

VLWHRISUHVHQWDWLRQ

2.2. Clinicopathologic features

&OLQLFDOO\3&)&/SUHVHQWFKDUDFWHULVWLFDOO\ZLWKVROLWDU\

RUJURXSHGSODTXHVDQGWXPRUVSUHIHUHQWLDOO\ORFDWHGRQ

WKH KHDG RU RQ WKH WUXQN DQG UDUHO\ DERXW  RI WKH

FDVHV  RQ WKH OHJV $ PXOWLIRFDO SUHVHQWDWLRQ ZLWK

VNLQ OHVLRQV ORFDOL]HG RQ GLIIHUHQW SDUWV RI WKH ERG\ LV

REVHUYHG LQ DSSUR[LPDWHO\  RI WKH SDWLHQWV EXW LV

QRW DVVRFLDWHG ZLWK D PRUH XQIDYRUDEOH SURJQRVLV

7KH FOLQLFDO EHKDYLRXU RI 3&)&/ LV VORZO\ SURJUHVVLYH

DQG H[WUDFXWDQHRXV GLVVHPLQDWLRQ LV XQFRPPRQ DERXW

 RI FDVHV  ,Q WKHVH UDUH FDVHV H[WUDFXWDQHRXV

PHWDVWDVHV VHHP WR GHYHORS SUHIHUHQWLDOO\ LQ WKH FHQWUDO

QHUYRXV V\VWHP 5HJDUGOHVV RI JURZWK SDWWHUQ WKH

QXPEHURIEODVWFHOOVRUWKHSUHVHQFHRIHLWKHUORFDOL]HG

RUPXOWLIRFDOGLVHDVH3&)&/KDYHDQH[FHOOHQWSURJQRVLV

ZLWKD\HDUVXUYLYDORIPRUHWKDQThe UHFRPPDQGHG PRGH RI WUHDWPHQW IRU WKHVH O\PSKRPDV

LV UDGLRWKHUDS\ +RZHYHU 3&)&/ SUHVHQWLQJ RQ WKH

OHJ DSSHDU WR KDYH D VLJQLÀFDQWO\ ZRUVH SURJQRVLV WKDQ

3&)&/SUHVHQWLQJRQWKHKHDGRUWUXQN7KHRSWLPDO

WUHDWPHQWRIWKHVH3&)&/SUHVHQWLQJRQWKHOHJ V UHTXLUHV

IXUWKHUVWXG\

 +LVWRSDWKRORJLFDOO\ 3&)&/ VKRZ QRGXODU WR GLIIXVH

LQÀOWUDWHVZLWKDOPRVWFRQVWDQWVSDULQJRIWKHHSLGHUPLV

7KHVH LQÀOWUDWHV PD\ KDYH D IROOLFXODU IROOLFXODU DQG

GLIIXVHJURZWKSDWWHUQDQGDUHFRPSRVHGRIDPL[WXUHRI

VPDOO DQG ODUJH FHQWURF\WHV UHODWLYHO\ IHZ FHQWUREODVWV

DQG PDQ\ UHDFWLYH 7FHOOV /DUJH FHQWURF\WHV RIWHQ

PXOWLOREDWHG DUH D FRPPRQ IHDWXUH 7KH QHRSODVWLF

FHOOV H[SUHVV &' &'D DQG PD\ VKRZ PRQRW\SLF

H[SUHVVLRQ RU DEVHQFH RI VXUIDFH LPPXQRJOREXOLQV $V

VKRZQLQFKDSWHU3&)&/FRQVLVWHQWO\H[SUHVV%FO

ZKHUHDV&'H[SUHVVLRQLVSDUWLFXODU\REVHUYHGLQFDVHV

ZLWK D IROOLFXODU JURZWK SDWWHUQ 8QOLNH QRGDO DQG

VHFRQGDU\FXWDQHRXVIROOLFXODUO\PSKRPD3&)&/XVXDOO\

GR QRW H[SUHVV %FO RU VKRZ IDLQW %FO LQ D PLQRULW\

RIWXPRUFHOOVDVGHPRQVWUDWHGE\WKHVWXG\SUHVHQWHGLQ

chapter 2 DQG RWKHU VWXGLHV7KH VWXG\ SUHVHQWHG LQ

chapter 7 DQG WKH VWXG\ E\ .RGDPD et al VKRZHG WKDW

VWDLQLQJ IRU DFWLYDWHG %FHOO DVVRFLDWHG PDUNHUV 0XP

,5)DQG)2;3LVQHJDWLYHLQWKHPDMRULW\RIFDVHV

:LWKLQWKH3&)&/JURXSH[SUHVVLRQRIQHLWKHU%FOQRU

0XP,5)RU)2;3DSSHDUVWREHUHODWHGWRDQLQIHULRU

FOLQLFDORXWFRPH

2.3. Genetic features

&KDUDFWHULVWLFDOO\ 3&)&/ GR QRW H[SUHVV %FO SURWHLQ

DQGGRQRWVKRZWKHW  +RZHYHUVHYHUDOUHFHQW

VWXGLHV KDYH UHSRUWHG WKH SUHVHQFH RI %FO H[SUHVVLRQ

DQGDW  LQDVLJQLÀFDQWPLQRULW\RI3&)&/PRVW

IUHTXHQWO\FDVHVZLWKDIROOLFXODUJURZWKSDWWHUQThe UHDVRQVIRUWKHVHGLVFUHSDQFLHVDUHQRWFOHDUEXWSRVVLEOH

H[SODQDWLRQVLQFOXGHGLIIHUHQFHVLQSDWLHQWVHOHFWLRQ HJ

LQFOXVLRQRISDWLHQWVZLWKVHFRQGDU\FXWDQHRXVGLVHDVH 

XVDJHRIGLIIHUHQW%FODQWLERGLHVDQGVFRULQJPHWKRGVRU

HYHQJHRJUDSKLFDOGLIIHUHQFHV,QDUHFHQWVWXG\6WUHXEHO

et al VXJJHVWHG WKDW WKHVH GLVFUHSDQW UHVXOWV FRXOG DOVR

EH DW OHDVW SDUWO\ GXH WR GLIIHUHQW GHWHFWLRQ PHWKRGV

7KH\GHPRQVWUDWHGWKHSUHVHQFHRIW  LQRXWRI

  3&)&/ZLWKD SDUWLDO IROOLFXODUJURZWKSDWWHUQ

E\ÁXRUHVFHQWin situK\EULGL]DWLRQ ),6+ DQDO\VLVXVLQJ

SUREHV VSDQQLQJ WKH HQWLUH IGH DQG BCL2 JHQHV EXW

ZHUH QRW DEOH WR FRQÀUP WKHLU UHVXOWV E\ WZR GLIIHUHQW

SRO\PHUDVH FKDLQ UHDFWLRQ 3&5  PHWKRGV )XUWKHU

VWXGLHVDUHZDUUDQWHGWRLQYHVWLJDWHWKHWUXHLQFLGHQFHRI

WKH W   LQ WKH HQWLUH VSHFWUXP RI 3&)&/ LQFOXGLQJ

FDVHVZLWKDGLIIXVHJURZWKSDWWHUQ

 ,Q chapters 5 and  PLFURDUUD\ DQG DUUD\EDVHG

FRPSDUDWLYH JHQRPLF K\EULGL]DWLRQ &*+  DQDO\VLV

VKRZHG FOHDUFXW GLIIHUHQFHV LQ JHQH H[SUHVVLRQ DQG

FKURPRVRPDODEHUUDWLRQVEHWZHHQ3&)&/ZLWKDGLIIXVH

(9)



ODUJH FHOO KLVWRORJ\ DQG 3&/%&/OHJ 7KHVH UHVXOWV

KDYH SURYLGHG VLJQLÀFDQW PROHFXODU JHQHWLF VXSSRUW IRU

WKHVXEGLYLVLRQRIWKHVHHQWLWLHVDFFRUGLQJWRWKHSUHYLRXV

(257& DSSURDFK DQG LWV UHFHQW DGRSWLRQ E\ WKH QHZ

:+2(257&FODVVLÀFDWLRQ$GGLWLRQDOO\WKHVHÀQGLQJV

LQGLFDWHWKDWDWOHDVWLQSDUWGLIIHUHQWJHQHWLFPHFKDQLVPV

DUHLQYROYHGLQ3&)&/DQG3&/%&/OHJ7KHPDLQUHVXOW

RIWKHPLFURDUUD\DQDO\VLVZDVWKDWKLHUDUFKLFDOFOXVWHULQJ

EDVHG RQ %FHOO SURÀOH VKRZHG GLVWLQFW JHQH H[SUHVVLRQ

SURÀOHV RI 3&)&/ ZLWK D GLIIXVH JURZWK SDWWHUQ DQG

3&/%&/OHJ )XUWKHU DQDO\VLV UHYHDOHG D VLPLODULW\ LQ

JHQH H[SUHVVLRQ SURÀOH EHWZHHQ 3&)&/ DQG *&%OLNH

'/%&/ FRUUHVSRQGLQJ WR D VXEVHW RI '/%&/ ZLWK D

PRUHIDYRUDEOHFOLQLFDORXWFRPH

 7KHWZRPDLQDEHUUDWLRQVLQ3&)&/GHPRQVWUDWHGE\

&*+DQDO\VLV chapter 6 ZHUHKLJKOHYHODPSOLÀFDWLRQ

RIFKURPRVRPHSFRQWDLQLQJERWKWKHBCL11ADQG

c-RELJHQHV RIFDVHV DQGGHOHWLRQRIFKURPRVRPH

TFRQWDLQLQJWKHORFXVRIimmunoglobulin heavy chain (IGH) RIFDVHV ,QWHUHVWLQJO\DPSOLÀFDWLRQV

RI WKH c-REL JHQH D PHPEHU RI WKH 1)Ʃ% IDPLO\ RI

WUDQVFULSWLRQIDFWRUVDUHDOVRH[FOXVLYHO\IRXQGLQQRGDO

*&%OLNH'/%&/+RZHYHUWKHRQFRJHQLFHIIHFWWKDW

LVFRQIHUUHGE\WKLVJHQHWLFDEHUUDWLRQLVXQFOHDUEHFDXVH

WKH*&%OLNH'/%&/WKDWKDYHDc-RELDPSOLÀFDWLRQGR

QRWKDYHLQFUHDVHGH[SUHVVLRQRI1)Ʃ%WDUJHWJHQHVDQG

FRQVHTXHQWO\ QR RYHUDFWLYDWLRQ RI WKH 1)Ʃ% SDWKZD\

ZKLFK PD\ UHVXOW LQ LQKLELWLRQ RI DSRSWRVLV DQG FHOOXODU

SUROLIHUDWLRQ 7KH GHOHWLRQ RI FKURPRVRPH T

FRQWDLQLQJWKHIGH JHQHLVLQDJUHHPHQWZLWKWKHUHVXOWV

RI WKH PLFURDUUD\ DQDO\VLV GHVFULEHG LQ chapter 5

sinceORVV RI P51$ H[SUHVVLRQ RI WKH IGH JHQH ORFXV

ZDV GHPRQVWUDWHG LQ 3&)&/ EXW QRW LQ 3&/%&/OHJ

)XUWKHUPRUH ORVV RI WKH IGH JHQH PLJKW H[SODLQ WKH

DEVHQFH RI VXUIDFH LPPXQRJOREXOLQ LQ VRPH 3&)&/ E\

LPPXQRKLVWRFKHPLVWU\

 ,Q FRQWUDVW WR 3&/%&/OHJ D UHFHQW VWXG\ GLG QRW

LGHQWLI\ FKURPRVRPDO WUDQVORFDWLRQV LQYROYLQJ WKH IGH

cMYCRUBCL6JHQHORFLLQ3&)&/ZLWKDGLIIXVHJURZWK

SDWWHUQ+RZHYHU6WUHXEHOet alIRXQGDFKURPRVRPDO

WUDQVORFDWLRQW  LQYROYLQJIGHDQGBCL6JHQHVLQD

PLQRULW\  RI3&)&/FDVHVZLWKDIROOLFXODUJURZWK

SDWWHUQ,QDUHFHQWVWXG\VRPDWLFPXWDWLRQVLQYROYLQJ

BCL6PAX5CMYCDQGRhoH/TTPJHQHVZHUHUHSRUWHG

LQ D VLJQLÀFDQW QXPEHU   RI 3&)&/ FDVHV $

VFKHPDWLF RYHUYLHZ RI WKHVH JHQHWLF DEHUUDWLRQV ZKLFK

PD\ EH LPSOLFDWHG LQ WKH SDWKRJHQHVLV RI 3&)&/ LV

SUHVHQWHGLQ)LJXUH

3ULPDU\FXWDQHRXVODUJH%FHOOO\PSKRPDOHJW\SH

'HÀQLWLRQDQGWHUPLQRORJ\

,QWKH(257&FODVVLÀFDWLRQWKHWHUPSULPDU\FXWDQHRXV

ODUJH %FHOO O\PSKRPD RI WKH OHJ 3&/%&/OHJ  ZDV

XVHG IRU &%&/ SUHVHQWLQJ ZLWK WXPRUV RQ WKH OHJV

DQG VKRZLQJ D GLIIXVH ODUJH %FHOO KLVWRORJ\ These O\PSKRPDV SDUWLFXODU\ DIIHFW HOGHUO\ IHPDOH SDWLHQWV

VKRZDKLJKHUUDWHRIUHODSVHDQGKDYHDPRUHXQIDYRUDEOH

SURJQRVLVDVFRPSDUHGWR3&)&/ZLWKDGLIIXVHJURZWK

SDWWHUQ \HDUVXUYLYDORIDSSUR[LPDWHO\DQGPRUH

WKDQ  UHVSHFWLYHO\  +LVWRORJLFDOO\ WKH\ VKRZ

D SUHGRPLQDQFH RI ODUJH URXQG %FHOOV FHQWUREODVWV

Figure 1. Main genetic aberrations of primary cutaneous follicle center lymphoma.

(10)



DQG LPPXQREODVWV  UDWKHU WKDQ ODUJH FOHDYHG FHOOV DQG

FRQVLVWHQWO\H[SUHVV%FO$OWKRXJKGHOLQHDWLRQRIWKHVH

O\PSKRPDVSULPDULO\EDVHGRQDQDWRPLFVLWHRISUHVHQWDWLRQ

KDVEHHQGLVSXWHGVHYHUDOFOLQLFRSDWKRORJLFDQGPROHFXODU

JHQHWLF VWXGLHV LQFOXGLQJ WKH VWXGLHV SUHVHQWHG LQ WKH

FKDSWHUVDQGRIWKHSUHVHQWWKHVLVKDYHSURYLGHG

IXUWKHUVXSSRUWIRUWKHGLVWLQFWLRQEHWZHHQ3&)&/ZLWKD

GLIIXVHJURZWKSDWWHUQDQG3&/%&/OHJ7KHUHVXOWV

RI WKH PLFURDUUD\ VWXG\ SUHVHQWHG LQ chapter 5 ZHUH RI

PDMRULPSRUWDQFHVLQFHLWZDVGHPRQVWUDWHGWKDW3&)&/

DQG 3&/%&/OHJ KDYH GLVWLQFW JHQH H[SUHVVLRQ SURÀOHV

ZKLFK SURYLGHG VLJQLÀFDQW VXSSRUW IRU WKHLU VXEGLYLVLRQ

IURPDPROHFXODUELRORJLFDOSRLQWRIYLHZ$GGLWLRQDOO\

WKH UHVXOWV VKRZHG WKDW 3&/%&/OHJ KDYH DQ$%&OLNH

'/%&/ H[SUHVVLRQ SURÀOH FRUUHVSRQGLQJ WR D VXEVHW RI

'/%&/ZLWKDSRRUSURJQRVLVZKHUHDV3&)&/VKRZHG

VLPLODULWLHV WR WKH *&%OLNH '/%&/ 7KH GLIIHUHQFH LQ

$%& YHUVXV *&%OLNH ZDV IXUWKHU FRQÀUPHG E\ WKH

DOPRVW FRQVWDQW H[SUHVVLRQ RI WKH$%&PDUNHUV 0XP

,5)DQG)2;3LQ3&/%&/OHJEXWQRWLQ3&)&/DV

REVHUYHGLQchapter 7

 %DVHGRQWKHUHVXOWVRIWKHVHVWXGLHVDQGRWKHUVWXGLHV

3&/%&/OHJLVDWSUHVHQWUHFRJQL]HGDVDVHSDUDWHHQWLW\

LQ WKH :+2(257& FODVVLÀFDWLRQ $FFRUGLQJ WR WKH

UHVXOWVRIDUHFHQWPXOWLFHQWHUVWXG\LWKDVEHFRPHHYLGHQW

WKDW FDVHV ZLWK D VLPLODU PRUSKRORJ\ SUHGRPLQDQFH RI

FRKHVLYH VKHHWV RI FHQWUREODVWV DQG LPPXQREODVWV 

LPPXQRSKHQRW\SH VWURQJ H[SUHVVLRQ RI %FO  DQG

SURJQRVLV PD\ DULVH DW RWKHU VLWHV WKDQ WKH OHJV48 )RU

WKLV UHDVRQ WKH WHUP SULPDU\ FXWDQHRXV ODUJH %FHOO

O\PSKRPD OHJ W\SH 3&/%&/ OHJ W\SH  LV FKRVHQ IRU

FDVHVSUHVHQWLQJRQWKHOHJVDQGVLPLODUFDVHVORFDWHGDW

RWKHU VLWHV &RQVHTXHQWO\ FDVHV SUHVHQWLQJ ZLWK WXPRUV

RQ WKH WUXQN VKRZLQJ D SUHGRPLQDQFH RI URXQG WXPRU

FHOOVZHUHFODVVLÀHGDV3&)&&/LQWKHSUHYLRXV(257&

FODVVLÀFDWLRQ EXW ZLOO EH FODVVLÀHG LQ WKH IXWXUH DV

3&/%&/OHJW\SH

 ,Q DGGLWLRQ WKH WHUP SULPDU\ FXWDQHRXV ODUJH %FHOO

O\PSKRPDRWKHU 3&/%&/RWKHU ZDVLQWURGXFHGLQWKH

:+2(257& FODVVLÀFDWLRQ 3&/%&/ RWKHU UHIHUV WR

UDUHFDVHVRIODUJH%FHOOO\PSKRPDVDULVLQJLQWKHVNLQ

ZKLFKGRQRWEHORQJWRWKHJURXSRI3&/%&/OHJW\SH

RU3&)&/ZLWKDGLIIXVHLQÀOWUDWLRQRIODUJHFOHDYHGFHOOV

7KHVH FDVHV LQFOXGH PRUSKRORJLFDO YDULDQWV RI '/%&/

VXFK DV DQDSODVWLF RU SODVPDEODVWLF VXEW\SHV 7FHOO

KLVWLRF\WHULFKODUJH%FHOOO\PSKRPDVDQGUDUHFDVHVRI

SULPDU\FXWDQHRXVLQWUDYDVFXODU%FHOOO\PSKRPD

3.2 Clinicopathologic features

&OLQLFDOO\ 3&/%&/ OHJ W\SH FKDUDFWHULVWLFDOO\ SUHVHQWV

ZLWKUDSLGO\JURZLQJHU\WKHPDWRXVWREOXLVKUHGWXPRUV

RQRQHRUERWK ORZHU OHJVEXWPD\DULVHDWRWKHUVLWHV

LQ DERXW  RI FDVHV 7KHVH O\PSKRPDV

SUHGRPLQDQWO\ DIIHFW HOGHUO\ SDWLHQWV DQG RFFXU PRUH

IUHTXHQWO\ LQ IHPDOHV WKDQ LQ PDOHV UDWLR   ,Q

FRQWUDVW ZLWK 3&)&/ WKHVH O\PSKRPDV PRUH RIWHQ

GLVVHPLQDWH WR H[WUDFXWDQHRXV VLWHV DQG KDYH D PRUH

XQIDYRUDEOH SURJQRVLV ZLWK D \HDU VXUYLYDO RI  7KH SUHVHQFH RI PXOWLSOH VNLQ OHVLRQV DW GLDJQRVLV LV DQ

DGYHUVH SURJQRVWLF IDFWRU LQ WKLV JURXS48 $QWKUDF\FOLQ

EDVHG FKHPRWKHUDS\ LV WKH VWDQGDUG WUHDWPHQW IRU WKLV

JURXS

 +LVWRSDWKRORJLFDOO\ WKHVH O\PSKRPDV VKRZ GLIIXVH

)LJXUH0DLQJHQHWLFDEHUUDWLRQVRISULPDU\FXWDQHRXVODUJH%FHOOO\PSKRPDOHJW\SH

(11)



LQÀOWUDWHV RIWHQ H[WHQGLQJ LQWR WKH VXEFXWDQHRXV WLVVXH

7KHLQÀOWUDWHVDUHFRPSRVHGRIDPRQRWRQRXVSRSXODWLRQ

RUFRQÁXHQWVKHHWVRIFHQWUREODVWVDQGLPPXQREODVWV7KH

WXPRUFHOOVH[SUHVV&'&'DDQGPRQRW\SLFV,JDQG

RUF,J7KHUHVXOWVRIchapters 2 and 7VKRZWKDW%FOLV

JHQHUDOO\H[SUHVVHGZKHUHDV&'H[SUHVVLRQLVXVXDOO\

DEVHQW 8QOLNH 3&)&/ WKH QHRSODVWLF FHOOV JHQHUDOO\

H[SUHVV %FO 0XP,5) DQG )2;3 DV VKRZQ LQ WKH

UHVXOWV RI FKDSWHUV   DQG $W SUHVHQW 0XP

,5) DQG )2;3 VHUYH DV QHZ YDOXDEOH GLDJQRVWLF

PDUNHUVIRU3&/%&/OHJW\SH7KHUHVXOWVRIRXUVWXGLHV

DQGWKHVWXG\RI.RGDPDet alGLGQRWVKRZDQ\SURJQRVWLF

VLJQLÀFDQFHRIWKHH[SUHVVLRQRI%FO0XP,5)DQG

)2;3ZLWKLQWKHJURXSRI3&/%&/OHJW\SH

3.3 Genetic features

5HFHQW PROHFXODU JHQHWLF VWXGLHV LQFOXGLQJ WKRVH

described in chapters 5 and 6 RI WKH SUHVHQW WKHVLV

UHYHDOHG VHYHUDO JHQHWLF DQG PROHFXODU OHVLRQV LQ

3&/%&/ OHJ W\SH 7KHVH JHQHWLF DEHUUDWLRQV UHVXOWLQJ

IURPGLIIHUHQWPROHFXODUPHFKDQLVPVPD\DOOFRQWULEXWH

WRWKHFRPSOH[SURFHVVRIWKHPROHFXODUSDWKRJHQHVLVRI

3&/%&/OHJW\SH )LJXUH 

 7KHSUHVHQFHRIFKURPRVRPDOWUDQVORFDWLRQVLQYROYLQJ

IGHCMYCDQGBCL6ZDVGHPRQVWUDWHGLQDERXW

RI WKH 3&/%&/ OHJ W\SH FDVHV $V D UHVXOW RI WKHVH

WUDQVORFDWLRQV GHUHJXODWLRQ RI BCL6 DQG CMYC, ERWK

SRWHQW RQFRJHQHV LQYROYHG LQ FHOO F\FOH UHJXODWLRQ

PD\ RFFXU DQG FRQWULEXWH WR XQFRQWUROOHG FHOOXODU

SUROLIHUDWLRQ 7KH FKURPRVRPDO WUDQVORFDWLRQ W   LV QRW IRXQG LQ 3&/%&/ OHJ W\SH 7KH VWURQJ %FO

 SURWHLQ H[SUHVVLRQ LQ WKHVH O\PSKRPDV PD\ DW OHDVW

LQ D VLJQLÀFDQW SURSRUWLRQ RI FDVHV UHVXOW IURP BCL2 JHQH DPSOLÀFDWLRQ DW FKURPRVRPH T ZKLFK ZDV

GHPRQVWUDWHG LQ  RI WKH FDVHV E\ DUUD\EDVHG &*+

DQDO\VLV SUHVHQWHG LQ chapter 6 )XUWKHUPRUH WKH

UHVXOWV RI WKLV VWXG\ VKRZHG MALT1 DPSOLÀFDWLRQV DW

WKHVDPHORFXVLQRIWKHFDVHVDQGDPSOLÀFDWLRQVRI

ERWKMALT1DQGBCL2JHQHVLQRIWKHFDVHVBCL2 DPSOLÀFDWLRQVZHUHSUHYLRXVO\UHSRUWHGLQDVPDOOVWXG\

E\ 0DR et al DOWKRXJK WKH DXWKRUV GLG QRW GLVWLQJXLVK

3&)&/ ZLWK D GLIIXVH SRSXODWLRQ RI ODUJH FOHDYHG FHOOV

DQG 3&/%&/ OHJ W\SH $ UHFHQW VWXG\ VKRZHG WKDW

T DPSOLÀFDWLRQV RFFXU PRUH IUHTXHQWO\ LQ $%&OLNH

'/%&/ WKDQ LQ *&%OLNH '/%&/ ZKLFK FRUURERUDWH

WKHSUHYLRXVO\REVHUYHG$%&SKHQRW\SHRI3&/%&/OHJ

W\SHDVVHVVHGE\PLFURDUUD\DQDO\VLV

 'HOHWLRQRIFKURPRVRPHSFRQWDLQLQJWKHCDKN2A (p16INK4A DQGCDKN2B (p15INK4B JHQHVGHPRQVWUDWHGLQ

 RI 3&/%&/ OHJ W\SH FDVHV UHSUHVHQWHG WKH PRVW

LQWHUHVWLQJÀQGLQJRIchapter 6VLQFHDOOSDWLHQWVZKR

GLHGDVDUHVXOWRIO\PSKRPDKDGDKRPR]\JRXVGHOHWLRQ

RI S  FDVHV  SURPRWHU K\SHUPHWK\ODWLRQ RI WKH

CDKN2A JHQH RQH FDVH  RU KHPL]\JRXV GHOHWLRQ RI

S FRPELQHG ZLWK PRQRDOOHOLF K\SHUPHWK\ODWLRQ

RQH FDVH  ,QDFWLYDWLRQ RI p16INK4A E\ HLWKHU GHOHWLRQ

RU PHWK\ODWLRQ FRXOG UHSUHVHQW DQ LPSRUWDQW DGYHUVH

SURJQRVWLFIDFWRUZLWKLQWKHJURXSRI3&/%&/OHJW\SH

 6HYHUDOVWXGLHVGHPRQVWUDWHGWKHSUHVHQFHRIVRPDWLFDOO\

PXWDWHG,JJHQHVFRPPRQO\XVHGDVDPDUNHURIJHUPLQDO

FHQWHUWUDQVLWDQGVRPDWLFPXWDWLRQVLQYROYLQJWKHBCL6 JHQH LQ 3&/%&/ OHJ W\SH 5HFHQWO\ DEHUUDQW

VRPDWLF PXWDWLRQV RI CMYC, RhoH/TTF DQG PAX5 ZHUH UHYHDOHG LQ D VLJQLÀFDQW SURSRUWLRQ   RI

3&/%&/ OHJ W\SH 7KHVH VRPDWLF PXWDWLRQV DIIHFWLQJ

SURWR RQFRJHQHVWKDWDUHLQYROYHGLQFHOOXODUSUROLIHUDWLRQ

GLIIHUHQWLDWLRQ DQG VLJQDO WUDQVGXFWLRQ RFFXU LQ DERXW

 RI QRGDO '/%&/ DV D UHVXOW RI PDOIXQFWLRQLQJ RI

WKH VRPDWLF K\SHUPXWDWLRQ PDFKLQHU\ DQG UHSUHVHQW DQ

DGGLWLRQDOPHFKDQLVPRIPDOLJQDQWWUDQVIRUPDWLRQ

 3&/%&/OHJW\SHDSSHDUWREHFORVHO\UHODWHGWR$%&

OLNH '/%&/ 7KH\ VKDUH QRW RQO\ VLPLODULWLHV LQ JHQH

H[SUHVVLRQSURÀOHEXWDOVRLQJHQRW\SLFDQGSKHQRW\SLF

IHDWXUHV7KHFHOORIRULJLQRI$%&OLNH'/%&/ZKLFK

DUHWHUPHGDVVXFKEHFDXVHWKH\UHVHPEOHPLWRJHQLFDOO\

DFWLYDWHG SHULSKHUDO %FHOOV DQG QRW JHUPLQDO FHQWHU %

FHOOVLVVWLOOLOOGHÀQHG,QWHUHVWLQJO\KLJKOHYHOVRIIGHM JHQH H[SUHVVLRQ LQ 3&/%&/ OHJ W\SH ZHUH FRQÀUPHG

E\ WKH H[FOXVLYH LPPXQRKLVWRFKHPLFDO H[SUHVVLRQ RI

VXUIDFH ,J0 EXW QRW RI ,J' ,J* RU ,J$ XQSXEOLVKHG

REVHUYDWLRQV  6LPLODU ÀQGLQJV ZHUH UHSRUWHG IRU$%&

OLNH'/%&/ZKLFKLQGLFDWHWKDWWKHVHO\PSKRPDVKDYH

QRWXQGHUJRQHFODVVVZLWFKUHFRPELQDWLRQDSKHQRPHQRQ

XQH[SODLQHG WKXVIDU 6LQFH $%&OLNH '/%&/ KDYH

VHYHUDO SODVPD FHOOV FKDUDFWHULVWLFV LQ WHUPV RI JHQH

H[SUHVVLRQLQFOXGLQJKLJKOHYHOVRILPPXQRJOREXOLQVDQG

SODVPDFHOOJHQHV VXFKDVMUM1/IRF4 DQG X-box protein 1(XBP1) DQGDORZHUOHYHORIBCL6FRPSDUHGWR*%&

OLNH'/%&/LWKDVEHHQVXJJHVWHGWKDWWKH\DUHGHULYHG

IURPDJHUPLQDOFHQWHUFHOOVXEVHWLQWUDQVLWLRQWRDSRVW

JHUPLQDOFHQWHUVWDWH$OWHUQDWLYHO\VLQFHVHYHUDOOLQHVRI

HYLGHQFHVXJJHVWWKDWVRPDWLFK\SHUPXWDWLRQDQGSODVPD

FHOOGLIIHUHQWLDWLRQFDQRFFXURXWVLGHWKHJHUPLQDOFHQWHU

LWLVSRVVLEOHWKDW$%&OLNH'/%&/LQFOXGLQJ3&/%&/

OHJW\SHDUHGHULYHGIURP%FHOOVWKDWKDYHQHYHUHQWHUHG

D JHUPLQDO FHQWHU )XWXUH VWXGLHV DUH ZDUUDQWHG WR

IXUWKHUHOXFLGDWHWKHFHOOXODUGHULYDWLRQRI3&/%&/OHJ

W\SHDQGLWVFRPSOH[PROHFXODUSDWKRJHQHVLV

4. Conclusions and perspectives

7KH VWXGLHV GHVFULEHG LQ WKLV WKHVLV KDYH UHVXOWHG LQ D

EHWWHU GHÀQLWLRQ RI FOLQLFRSDWKRORJLF DQG PROHFXODU

JHQHWLFIHDWXUHVRIWKHGLIIHUHQWW\SHVRI&%&/)RUWKDW

UHDVRQWKHVHUHVXOWVKDYHPDGHDQLPSRUWDQWFRQWULEXWLRQ

WR WKH QHZ FRQVHQVXV :+2(257& FODVVLÀFDWLRQ 7KH

(12)



EDVLV IRU WKHVH QHZ LQVLJKWV LV WKDW DYDLODEOH DQG QHZ

GDWDIDFLOLWDWHWKHGLIIHUHQWLDOGLDJQRVLVEHWZHHQ3&)&/

DQG3&0=/DQGLQGLFDWHWKDW3&)&/DQG3&/%&/OHJ

W\SHDUHLQGHHGGLIIHUHQWFOLQLFRSDWKRORJLFDOHQWLWLHVZLWK

WKHLURZQJHQRW\SLFDQGSKHQRW\SLFFKDUDFWHULVWLFV7KH

QHZ GHÀQLWLRQV ZLOO DOORZ D EHWWHU GLVWLQFWLRQ EHWZHHQ

LQGROHQW DQG PRUH DJJUHVVLYH W\SHV RI &%&/ DQG

IDFLOLWDWH WKH GHFLVLRQ ZKHWKHU UDGLRWKHUDS\ RU V\VWHPLF

FKHPRWKHUDS\VKRXOGEHFKRVHQDVDÀUVWOLQHWUHDWPHQW

/DUJH FOLQLFRSDWKRORJLF VWXGLHV DUH DW SUHVHQW UHTXLUHG

WR YDOLGDWH WKH FXUUHQW SURSRVDOV DQG LQ SDUWLFXODU WR

LQYHVWLJDWH WKH GLDJQRVWLF DQG SURJQRVWLF VLJQLÀFDQFH

RI WKH FXUUHQWO\ DYDLODEOH LPPXQRSKHQRW\SLF PDUNHUV

LQFOXGLQJ%FO0XP,5)DQG)2;35HFHQWVWXGLHV

KDYHDOUHDG\VWDUWHGWRHYDOXDWHWKHFOLQLFDOVLJQLÀFDQFH

RIWKH:+2(257&FODVVLÀFDWLRQEXWVKRZHGGLIIHUHQW

LQWHUSUHWDWLRQV RI WKH 3&/%&/ RWKHU FDWHJRU\ ZKLFK

IXUWKHU HPSKDVL]HV WKH QHFHVVLW\ IRU IXWXUH PXOWLFHQWHU

VWXGLHV

 7KHREVHUYHGGLIIHUHQFHVLQJHQHH[SUHVVLRQDQGJHQHWLF

DEHUUDWLRQV EHWZHHQ 3&)&/ DQG 3&/%&/ OHJ W\SH GR

QRW RQO\ SURYLGH IXUWKHU VXSSRUW IRU WKHLU GLVWLQFWLRQ

LQ VHSDUDWH HQWLWLHV EXW DOVR LQGLFDWH WKDW GLIIHUHQW

PROHFXODUPHFKDQLVPVSOD\DUROHLQWKHSDWKRJHQHVLVDQG

ELRORJLFDOEHKDYLRXURIWKHVHO\PSKRPDV7KHH[FOXVLYH

LGHQWLÀFDWLRQ RI ORVV RI CDKN2A (p16INK4A  LQ D VXEVHW

RI3&/%&/OHJW\SHZLWKDIDWDOFOLQLFDORXWFRPHLVD

SURPLVLQJDGYHUVHSURJQRVWLFIDFWRULQWKLVJURXSZKLFK

UHTXLUHVYDOLGDWLRQLQODUJHUVHULHVRISDWLHQWV6XEVHTXHQW

PROHFXODUJHQHWLFVWXGLHVVKRXOGEHDLPHGDWGHOLQHDWLRQ

RIJHQHWLFOHVLRQVWKDWDUHHVVHQWLDOIRUWKHGHYHORSPHQW

DQGSURJUHVVLRQRI&%&/,WPD\EHH[SHFWHGWKDWWKHVH

VWXGLHV PD\ LGHQWLI\ QRYHO GLDJQRVWLF DQG SURJQRVWLF

PDUNHUVDQGPD\XOWLPDWHO\OHDGWRDUHÀQHGFODVVLÀFDWLRQ

DQG LPSURYHG WKHUDSLHV IRU WKLV SDUWLFXODU JURXS RI

H[WUDQRGDO%FHOOQRQ+RGJNLQ·VO\PSKRPDV

References

 :LOOHP]H5.HUO+6WHUU\:HWDO(257&FODVVLÀFDWLRQ

IRU SULPDU\ FXWDQHRXV O\PSKRPDV $ SURSRVDO IURP WKH

&XWDQHRXV /\PSKRPD 6WXG\ *URXS RI WKH (XURSHDQ

2UJDQL]DWLRQ IRU 5HVHDUFK DQG 7UHDWPHQW RI &DQFHU

(257& %ORRG

 -DIIH (6 +DUULV 1/ 6WHLQ + 9DUGLPDQ -: (GV  :RUOG

+HDOWK 2UJDQL]DWLRQ &ODVVLÀFDWLRQ RI 7XPRXUV 3DWKRORJ\

DQG*HQHWLFVRI7XPRXUVRI+DHPDWRSRLHWLFDQG/\PSKRLG

7LVVXHV,$5&3UHVV/\RQ

 :LOOHP]H 5 -DIIH (6 %XUJ * HW DO :+2(257&

FODVVLÀFDWLRQ IRU FXWDQHRXV O\PSKRPDV %ORRG



 6WDQVIHOG $* 'LHEROG - .DSDQFL < HW DO 8SGDWHG .LHO

FODVVLÀFDWLRQIRUO\PSKRPDV/DQFHW

 6ODWHU'10$/7DQG6$/7WKHFOXHWRFXWDQHRXV%FHOO

O\PSKRSUROLIHUDWLYHGLVHDVH%U-'HUPDWRO



 +RHIQDJHO--9HUPHHU0+-DQVHQ30HWDO%FO%FO

DQG&'H[SUHVVLRQLQFXWDQHRXV%FHOOO\PSKRPDIXUWKHU

VXSSRUW IRU D IROOLFOH FHQWHU FHOO RULJLQ DQG GLIIHUHQWLDO

GLDJQRVWLF VLJQLÀFDQFH %U - 'HUPDWRO 



 GH/HYDO/+DUULV1//RQJWLQH-HWDO&XWDQHRXV%FHOO

O\PSKRPDV RI IROOLFXODU DQG PDUJLQDO ]RQH W\SHV 8VH RI

%FO&'%FODQG&'LQGLIIHUHQWLDOGLDJQRVLVDQG

FODVVLÀFDWLRQ$P-6XUJ3DWKRO

 +RHIQDJHO -- 9HUPHHU 0+ -DQVHQ 30 HW DO 3ULPDU\

FXWDQHRXV PDUJLQDO ]RQH %FHOO O\PSKRPD &OLQLFDO

DQG WKHUDSHXWLF IHDWXUHV LQ  FDVHV $UFK 'HUPDWRO



 5LMODDUVGDP-8YDQGHU3XWWH6&-%HUWL(HWDO&XWDQHRXV

LPPXQRF\WRPDV $ FOLQLFRSDWKRORJLF VWXG\ RI  FDVHV

+LVWRSDWKRORJ\

 &HUURQL/6LJQRUHWWL6+|ÁHU*HWDO3ULPDU\FXWDQHRXV

PDUJLQDO]RQH%FHOOO\PSKRPDDUHFHQWO\GHVFULEHGHQWLW\

RIORZJUDGHPDOLJQDQWFXWDQHRXV%FHOOO\PSKRPD$P-

6XUJ3DWKRO

 %DLOH\ (0 )HUU\ -$ +DUULV 1/ HW DO 0DUJLQDO ]RQH

O\PSKRPD ORZJUDGH %FHOO O\PSKRPD RI PXFRVD

DVVRFLDWHGO\PSKRLGWLVVXH RIVNLQDQGVXEFXWDQHRXVWLVVXH

D VWXG\ RI  SDWLHQWV $P - 6XUJ 3DWKRO 



 /H%RLW3(0F1XWW165HHG-$HWDO3ULPDU\FXWDQHRXV

LPPXQRF\WRPD D %FHOO O\PSKRPD WKDW FDQ HDVLO\ EH

PLVWDNHQ IRU FXWDQHRXV O\PSKRLG K\SHUSODVLD $P - 6XUJ

3DWKRO

 /L&,QDJDNL+.XR7HWDO3ULPDU\FXWDQHRXVPDUJLQDO

]RQH %FHOO O\PSKRPD$ PROHFXODU DQG FOLQLFRSDWKRORJLF

VWXG\RI$VLDQFDVHV$P-6XUJ3DWKRO



 &HUURQL/=|FKOLQJ13W]%HWDO,QIHFWLRQE\%RUUHOLD

EXUJGRUIHULDQGFXWDQHRXV%FHOOO\PSKRPD-&XWDQ3DWKRO



 *RRGODG -5 'DYLGVRQ 00 +ROORZRRG . HW DO 3ULPDU\

FXWDQHRXV %FHOO O\PSKRPD DQG %RUUHOLD EXUJGRUIHUL

LQIHFWLRQLQSDWLHQWVIURPWKH+LJKODQGVRI6FRWODQG$P-

6XUJ3DWKRO

 :RRG*6.DPDWK19*XLWDUW-HWDO$EVHQFHRI%RUUHOLD

EXUJGRUIHUL'1$LQFXWDQHRXV%FHOOO\PSKRPDVIURPWKH

8QLWHG6WDWHV-&XWDQ3DWKRO

 3DFKQHU $5 'DLO ' %DL < HW DO *HQRW\SH GHWHUPLQHV

SKHQRW\SH LQ H[SHULPHQWDO /\PH ERUUHOLRVLV $QQ 1HXURO



 +RHIQDJHO -- 0XOGHU 006 'UHHI ( HW DO ([SUHVVLRQ RI

%FHOO WUDQVFULSWLRQ IDFWRUV LQ SULPDU\ FXWDQHRXV %FHOO

O\PSKRPD0RG3DWKRO

 .WWLQJ%%RQVPDQQ*0HW]H'HWDO%RUUHOLDEXUJGRUIHUL

DVVRFLDWHG SULPDU\ FXWDQHRXV %FHOO O\PSKRPD FRPSOHWH

FOHDULQJ RI VNLQ OHVLRQV DIWHU DQWLELRWLF SXOVH WKHUDS\ RU

LQWUDOHVLRQDO LQMHFWLRQ RI LQWHUIHURQ DOSKDD - $P $FDG

'HUPDWRO

 :ROOLQD 8 +DKQIHOG 6 .RVPHKO 3ULPDU\ FXWDQHRXV

PDUJLQDO FHQWHU O\PSKRPDFRPSOHWH UHPLVVLRQ LQGXFHG E\

(13)



LQWHUIHURQDOSKDD-&DQFHU5HV&OLQ2QFRO



 6RGD5&RQVWDQ]R$&DQWRQHWWL0HWDO6\VWHPLFWKHUDS\

RISULPDU\FXWDQHRXV%FHOOO\PSKRPDPDUJLQDO]RQHW\SH

ZLWKULWX[LPDEDFKLPHULFDQWL&'PRQRFORQDODQWLERG\

$FWD'HUP9HQHUHRO

 *HOOULFK60XFKH-03HO]HU.HWDO$QWL&'DQWLERGLHV

IRUSULPDU\FXWDQHRXV%FHOOO\PSKRPDSUHOLPLQDU\UHVXOWV

LQGHUPDWRORJLFSDWLHQWV+DXWDU]W

 )LQN3XFKHV 5 :ROI , =DODXGHN , HW DO 7UHDWPHQW RI

SULPDU\FXWDQHRXV%FHOOO\PSKRPDZLWKULWX[LPDE-$P

$FDG'HUPDWRO

 &R]]LR$.HPSI:6FKPLG0H\HU5HWDO,QWUDOHVLRQDO

ORZGRVH LQWHUIHURQ ƠD WKHUDS\ IRU SULPDU\ FXWDQHRXV

PDUJLQDO ]RQH %FHOO O\PSKRPD /HXN /\PSKRPD



 6XDUH])/RUWKRODU\2+HUPLQH2HWDO,QIHFWLRQDVVRFLDWHG

O\PSKRPDVGHULYHGIURPPDUJLQDO]RQH%FHOOVDPRGHORI

DQWLJHQGULYHQO\PSKRSUROLIHUDWLRQ%ORRG



 %HUWRQL)=XFFD('HOYLQJGHHSHULQWR0$/7O\PSKRPD

ELRORJ\-&OLQ,QYHVW

 +DUULV1/6WHLQ+&RXSODQG6(HWDO1HZDSSURDFKHVWR

O\PSKRPDGLDJQRVLV+HPDWRORJ\

 $DUWV:0:LOOHP]H5%HQGH5-HWDO9+JHQHDQDO\VLVRI

SULPDU\FXWDQHRXV%FHOOO\PSKRPD(YLGHQFHIRURQJRLQJ

VRPDWLF K\SHUPXWDWLRQ DQG LVRW\SH VZLWFKLQJ %ORRG



 )UDQFR 5 &DPDFKR ), )HUQDQGH]9D]TXH]$ HW DO IgVH DQGbcl6VRPDWLFPXWDWLRQDQDO\VLVUHYHDOVWKHKHWHURJHQHLW\

RIFXWDQHRXV%FHOOO\PSKRPDDQGLQGLFDWHVWKHSUHVHQFHRI

XQGLVFORVHGDQWLJHQV0RG3DWKRO

 %DKOHU ': .LP %. *DR $ HW DO $QDO\VLV RI

LPPXQRJOREXOLQ 9+ JHQHV VXJJHVWV FXWDQHRXV PDUJLQDO

]RQH %FHOO O\PSKRPDV UHFRJQLVH VLPLODU DQWLJHQV %U -

+DHPDWRO

 )DULQKD3*DVFR\QH50ROHFXODUSDWKRJHQHVLVRI0XFRVD

$VVRFLDWHG /\PSKRLG 7LVVXH /\PSKRPD - &OLQ 2QFRO



 1DNDJDZD06HWR0+RVRNDZD<0ROHFXODUSDWKRJHQHVLV

RI 0$/7 O\PSKRPD WZR VLJQDOLQJ SDWKZD\V XQGHUO\LQJ

WKH DQWLDSRSWRWLF HIIHFW RI $3,0$/7 IXVLRQ SURWHLQ

/HXNHPLD

 6FKUHXGHU0,+RHIQDJHO---DQVHQ30HWDO),6+DQDO\VLV

RI0$/7O\PSKRPDVSHFLÀFWUDQVORFDWLRQVDQGDQHXSORLG\

LQ SULPDU\ FXWDQHRXV PDUJLQDO ]RQH O\PSKRPD - 3DWKRO



 6WUHXEHO%/DPSUHFKW$'LHUODPP-HWDO7  TT  LQYROYLQJ ,*+ DQG 0$/7 LV D IUHTXHQW FKURPRVRPDO

DEHUUDWLRQ LQ 0$/7 O\PSKRPD %ORRG 



 0XUJD 3HQDV (0 +LQ] . 5RVHU . HW DO 7UDQVORFDWLRQV

W  TT  DQG W  TT  DUH WKH PDLQ

FKURPRVRPDO DEQRUPDOLWLHV LQYROYLQJ 0/70$/7 LQ

0$/7O\PSKRPDV/HXNHPLD

 6WUHXEHO%9LQDW]HU8/DPSUHFKW$HWDO7  ST  LQYROYLQJ,*+DQG)2;3LVDQRYHOUHFXUUHQWFKURPRVRPDO

DEHUUDWLRQ LQ 0$/7 O\PSKRPD /HXNHPLD 



 :LOOHP]H 5 0HLMHU &-/0 6HQWLV +- HW DO 3ULPDU\

FXWDQHRXV ODUJH FHOO O\PSKRPDV RI IROOLFXODU FHQWHU FHOO

RULJLQ-$P$FDG'HUPDWRO

 *DUFLD&):HLVV/0:DUQNH5$HWDO&XWDQHRXVIROOLFXODU

O\PSKRPD$P-6XUJ3DWKRO

 %HUWL($OHVVL(&DSXWR5HWDO5HWLFXORKLVWLRF\WRPDRI

WKHGRUVXP-$P$FDG'HUPDWRO

 6DQWXFFL 0 3LPSLQHOOL 1$UJDQLQL / 3ULPDU\ FXWDQHRXV

%FHOO O\PSKRPD$ XQLTXH W\SH RI ORZJUDGH O\PSKRPD

&OLQLFRSDWKRORJLF DQG LPPXQRORJLF VWXG\ RI  FDVHV

&DQFHU

 5LMODDUVGDP-87RRQVWUD-0HLMHU&-/0HWDO7UHDWPHQW

RI SULPDU\ FXWDQHRXV O\PSKRPDV RI IROOLFXODU FHQWHU FHOO

RULJLQ $ FOLQLFDO IROORZXS VWXG\ RI  SDWLHQWV WUHDWHG

ZLWK UDGLRWKHUDS\ RU SRO\FKHPRWKHUDS\ - &OLQ 2QFRO



 &KLOG )- 5XVVHOO-RQHV 5 :RROIRUG $- HW DO $EVHQFH

RI WKH W   WUDQVORFDWLRQ LQ SULPDU\ FXWDQHRXV %FHOO

O\PSKRPD%U-'HUPDWRO

 &HUURQL / 9RONHQDQGW 0 5LHJHU ( HW DO %FO SURWHLQ

H[SUHVVLRQ DQG FRUUHODWLRQ ZLWK WKH LQWHUFKURPRVRPDO

  WUDQVORFDWLRQ LQ FXWDQHRXV O\PSKRPDV DQG

SVHXGRO\PSKRPDV-,QYHVW'HUPDWRO

 &HUURQL / $U]EHUJHU ( 3W] % HW DO 3ULPDU\ FXWDQHRXV

IROOLFOHFHQWHUFHOOO\PSKRPDZLWKIROOLFXODUJURZWKSDWWHUQ

%ORRG

 *HHOHQ )$0- 9HUPHHU 0+ 0HLMHU &-/0 HW DO %FO

H[SUHVVLRQ LQ SULPDU\ FXWDQHRXV ODUJH %FHOO O\PSKRPD LV

VLWHUHODWHG-&OLQ2QFRO

 *HOOULFK65XW]6*ROHPERZVNL6HWDO3ULPDU\FXWDQHRXV

IROOLFOHFHQWHUFHOOO\PSKRPDVDQGODUJH%FHOOO\PSKRPDV

RIWKHOHJGHVFHQGIURPJHUPLQDOFHQWHUFHOOV$VLQJOHFHOO

SRO\PHUDVH FKDLQ UHDFWLRQ DQDO\VLV - ,QYHVW 'HUPDWRO



 +RHIQDJHO--'LMNPDQ5%DVVR.HWDO'LVWLQFWW\SHVRI

SULPDU\FXWDQHRXVODUJH%FHOOO\PSKRPDLGHQWLÀHGE\JHQH

H[SUHVVLRQSURÀOLQJ%ORRG

 *UDQJH)%HNNHQN0::HFKVOHU-HWDO3URJQRVWLFIDFWRUV

LQ SULPDU\ FXWDQHRXV ODUJH %FHOO O\PSKRPDV D (XURSHDQ

PXOWLFHQWHUVWXG\-&OLQ2QFRO

 .RGDPD . 0DVVRQH & &KRWW$ HW DO 3ULPDU\ FXWDQHRXV

ODUJH %FHOO O\PSKRPDV FOLQLFRSDWKRORJLF IHDWXUHV

FODVVLÀFDWLRQ DQG SURJQRVWLF IDFWRUV LQ D ODUJH VHULHV RI

SDWLHQWV%ORRG

 %HNNHQN 0: 3RVWPD 7- 0HLMHU &-/0 HW DO )UHTXHQF\

RIFHQWUDOQHUYRXVV\VWHPLQYROYHPHQWLQSULPDU\FXWDQHRXV

%FHOOO\PSKRPD&DQFHU

 .LP%.6XUWL83DQG\D$*HWDO3ULPDU\DQGVHFRQGDU\

FXWDQHRXVGLIIXVHODUJH%FHOOO\PSKRPDV$P-6XUJ3DWKRO



 *RRGODG -5 .UDMHZVNL $6 %DWRQH 3- HW DO 3ULPDU\

FXWDQHRXV IROOLFXODU O\PSKRPD D FOLQLFRSDWKRORJLF DQG

PROHFXODUVWXG\RIFDVHVLQVXSSRUWRI DGLVWLQFWHQWLW\

$P-6XUJ3DWKRO

 0LU]D , 0DFSKHUVRQ 6 3DSURVNL 6 HW DO 3ULPDU\

FXWDQHRXV IROOLFXODU O\PSKRPD DQ DVVHVVPHQW RI FOLQLFDO

KLVWRSDWKRORJLFLPPXQRSKHQRW\SLFDQGPROHFXODUIHDWXUHV

-&OLQ2QFRO

 *RRGODG -5 .UDMHZVNL $6 %DWVWRQH 3- HW DO 3ULPDU\

(14)



FXWDQHRXV GLIIXVH ODUJH %FHOO O\PSKRPD SURJQRVWLF

VLJQLÀFDQFH DQG FOLQLFRSDWKRORJLF VXEW\SHV $P - 6XUJ

3DWKRO

 %HUJPDQ5.XUWLQ3-*LEVRQ/(HWDO&OLQLFRSDWKRORJLF

LPPXQRSKHQRW\SLF DQG PROHFXODU FKDUDFWHUL]DWLRQ RI

SULPDU\ FXWDQHRXV IROOLFXODU %FHOO O\PSKRPD $UFK

'HUPDWRO

 $JXLOHUD167RPDV]HZVNL000RDG-&HWDO&XWDQHRXV

IROOLFOH FHQWHU O\PSKRPD D FOLQLFRSDWKRORJLF VWXG\ RI 

FDVHV0RG3DWKRO

 6WUHXEHO % 6FKHXFKHU % 9DOHQFDN - HW DO 0ROHFXODU

F\WRJHQHWLFHYLGHQFHRIW  IGH;BCL2 LQDVXEVWDQWLDO

SURSRUWLRQRISULPDU\FXWDQHRXVIROOLFOHFHQWHUO\PSKRPDV

$P-6XUJ3DWKRO

 'LMNPDQ 5 7HQVHQ &3 -RUGDQRYD (6 HW DO $UUD\EDVHG

FRPSDUDWLYH JHQRPLF K\EULGL]DWLRQ DQDO\VLV UHYHDOV UHFXU

UHQWFKURPRVRPDODOWHUDWLRQVDQGSURJQRVWLFSDUDPHWHUVLQ

SULPDU\ FXWDQHRXV ODUJH %FHOO O\PSKRPD - &OLQ 2QFRO



 5RVHQZDOG$:ULJKW*&KDQ:&HWDO7KHXVHRIPROHFXODU

SURÀOLQJWRSUHGLFWVXUYLYDODIWHUFKHPRWKHUDS\IRUGLIIXVH

ODUJH %FHOO O\PSKRPD 1 (QJO - 0HG 



 6iQFKH]%HDWR06iQFKH]$JXLOHUD$3LULV0&HOOF\FOH

GHUHJXODWLRQ LQ %FHOO O\PSKRPDV %ORRG 



 +RXOGVZRUWK-2OVKHQ$%&DWWRUHWWL*HWDO5HODWLRQVKLS

EHWZHHQ5(/DPSOLÀFDWLRQ5(/IXQFWLRQDQGFOLQLFDODQG

ELRORJLFDOIHDWXUHVLQGLIIXVHODUJH%FHOOO\PSKRPDV%ORRG



 +DOOHUPDQQ & .DXQH .0 1HXPDQQ & HW DO 0ROHFXODU

F\WRJHQHWLFDQDO\VLVRIFKURPRVRPDOEUHDNSRLQWVLQWKH,*+

0<&%&/DQG0$/7JHQHORFLLQSULPDU\FXWDQHRXV%

FHOOO\PSKRPDV-,QYHVW'HUPDWRO

 'LMNPDQ57HQVHQ&3%XHWWQHU0HWDO3ULPDU\FXWDQHRXV

IROOLFOHFHQWHUO\PSKRPDDQGSULPDU\FXWDQHRXVODUJH%FHOO

O\PSKRPD OHJ W\SH DUH ERWK WDUJHWHG E\ DEHUUDQW VRPDWLF

K\SHUPXWDWLRQ EXW GHPRQVWUDWH GLIIHUHQWLDO H[SUHVVLRQ RI

$,'%ORRG

 9HUPHHU0+*HHOHQ)$0-YDQ+DVHOHQ&:HWDO3ULPDU\

FXWDQHRXV ODUJH %FHOO O\PSKRPDV RI WKH OHJV $ GLVWLQFW

W\SH RI FXWDQHRXV %FHOO O\PSKRPD ZLWK DQ LQWHUPHGLDWH

SURJQRVLV$UFK'HUPDWRO

 =LQ]DQL 3/ 4XDJOLQR 3 3LPSLQHOOL 1 HW DO 3URJQRVWLF

IDFWRUVLQSULPDU\FXWDQHRXV%FHOOO\PSKRPD7KH,WDOLDQ

6WXG\ *URXS IRU &XWDQHRXV /\PSKRPDV - &OLQ 2QFRO



 0DR;/LOOLQJWRQ'&KLOG)HWDO&RPSDUDWLYHJHQRPLF

K\EULGL]DWLRQDQDO\VLVRISULPDU\FXWDQHRXV%FHOOO\PSKR

PDV,GHQWLÀFDWLRQRIFRPPRQJHQHWLFDOWHUDWLRQVLQGLVHDVH

SDWKRJHQHVLV *HQHV &KURPRVRPHV &DQFHU 



 7DJDZD + 6XJXUR 0 7VX]XNL 6 HW DO &RPSDULVRQ RI

JHQRPH SURÀOHV IRU LGHQWLÀFDWLRQ RI GLVWLQFW VXEJURXSV RI

GLIIXVH ODUJH %FHOO O\PSKRPD %ORRG 



 3DXOOL 0 9LJOLR $ 9LYHQ]D ' HW DO 3ULPDU\ FXWDQHRXV

ODUJH %FHOO O\PSKRPD RI WKH OHJ KLVWRJHQHWLF DQDO\VLV

RI D FRQWURYHUVLDO FOLQLFRSDWKRORJLF HQWLW\ +XP 3DWKRO



 3DVTXDOXFFL / 1HXPHLVWHU 3 *RRVVHQV 7 HW DO +\SHU

PXWDWLRQRIPXOWLSOHSURWRRQFRJHQHVLQ%FHOOGLIIXVHODUJH

FHOOO\PSKRPDV1DWXUH

 $OL]DGHK$$(LVHQ0%'DYLV5(HWDO'LVWLQFWW\SHVRI

GLIIXVHODUJH%FHOOO\PSKRPDLGHQWLÀHGE\JHQHH[SUHVVLRQ

SURÀOLQJ1DWXUH

 6KDIIHU $/ 5RVHQZDOG $ 6WDXGW /0 /\PSKRLG

PDOLJQDQFLHV 7KH GDUN VLGH RI %FHOO GLIIHUHQWLDWLRQ 1DW

5HY,PPXQRO

 :LOOLDP - (XOHU & &KULVWHQVHQ 6 HW DO (YROXWLRQ RI

DXWRDQWLERG\ UHVSRQVHV YLD VRPDWLF K\SHUPXWDWLRQ RXWVLGH

RIJHUPLQDOFHQWHUV6FLHQFH

 :LOOLDP-(XOHU&6KORPFKLN06KRUWOLYHGSODVPDEODVWV

GRPLQDWHWKHHDUO\VSRQWDQHRXVUKHXPDWRLGIDFWRUUHVSRQVH

'LIIHUHQWLDWLRQ SDWKZD\V K\SHUPXWDWLQJ FHOO W\SHV DQG

DIÀQLW\PDWXUDWLRQRXWVLGHWKHJHUPLQDOFHQWHU-,PPXQRO



 :DOVK6+5RVHQTXLVW5,PPXQRJOREXOLQJHQHDQDO\VLV

RIPDWXUH%FHOOPDOLJQDQFLHVUHFRQVLGHUDWLRQRIFHOOXODU

RULJLQDQGSRWHQWLDODQWLJHQLQYROYHPHQWLQSDWKRJHQHVLV

0HG2QFRO

Referenties

GERELATEERDE DOCUMENTEN

High-resolution analysis of chromosome 2 demonstrating (A) the fre- quency of gains and losses in a typical primary cutaneous follicle center lymphoma patient, (B) the amplification

The tumor cells expressed early B-cell transcription factors Pax-5 and PU.1, germinal center marker Bcl-6, transcrip- tion factors Oct2 and BOB.1, but not the plasma cell and

YHQ LQ KRRIGVWXN  ZHUG ELM  YDQ GH SDWLsQWHQ PHW. HHQ3&amp;0=/HHQDVVRFLDWLHPHWHHQBorrelia burgdorferi LQIHFWLH JHYRQGHQ 5HFHQW ]LMQ ELM

1D KHW GRRUORSHQ YDQ GH FRDVVLVWHQWVFKDSSHQ ZHUG LQ  KHW DUWVH[DPHQ FXP ODXGH  EHKDDOG ,Q.

Gezien het indolente klinische beloop en de uitstekende prognose van het primair cutane marginale zone B-cel lymfoom, dient bij de behandeling een goede balans te worden gezocht

PCLBCL-leg Primary cutaneous large B-cell lymphoma of the leg PCLBCL, LT Primary cutaneous diffuse large B-cell lymphoma, leg type PCLBCL, other Primary cutaneous diffuse large

3 In this classification three main types of CBCL are described: primary cutaneous marginal zone B-cell lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL)

These 300 cases were reclassified as PCMZL, PCFCL or PCLBCL, LT following the WHO-EORTC classification, and as extranodal marginal zone B-cell lymphoma (EMZL), cutaneous