Colorectal carcinogenesis in patients with primary sclerosing cholangitis and inflammatory bowel disease = 2005-Dissertação

8/2/2019 Colorectal carcinogenesis in patients with primary sclerosing cholangitis and inflammatory bowel disease = 2005-Di

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Colocl ccinognsis in pins

wih pimy sclosing cholngiis nd

inmmoy bowl diss

M.M.H. Classn

proefschrift Marian.indd 1 10-10-2010 20:55:46


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MMH Claessen was kindly supported by an unrestricted grant from Janssen-Cilag, Tilburg, the

Netherlands.

Financial support for the publication of this theses was kindly provided by:

Copyrigh Marian Classn

ISBN: 9789461081049

Lay ou: www.wnzid.nl

Covr: www.groozus.nl

Prind by: Gildprin Dukkrijn BV



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Poschi

r vrkrijging van d graad van docor aan d Univrsii Urch

op gzag van d rcor magnicus, pro.dr. J.C. Soo,

ingvolg h bslui van h collg voor promois in h opnbaar

vrddign op dinsdag 23 novmbr 2010 ds middags 4.15 uur

door

Min Mi Hubin Clssn

gborn op 3 novmbr 1981 Humn

Colocl ccinognsis in pins

wih pimy sclosing cholngiis nd

inmmoy bowl diss

Colorcal carcinogns in painn m primair

sclrosrnd cholangiis n infammaoir darmzikn

(m n samnvaing in h Ndrlands)



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Conns

Chapr 1 Gnral Inroducion 7

Chapr 2 IBD-rlad Carcinoma and Lymphoma 15

Chapr 3 High Liim Risk o Cancr in Primary Sclrosing Cholangiis 33

Chapr 4 Mor Righ-sidd IBD-associad Colorcal Cancr in Pains

wih Primary Sclrosing Cholangiis

47

Chapr 5 Microsalli Insabiliy in Pains wih Primary Sclrosing

Cholangiis and Coliis-associad Colorcal Cancr

59

Chapr 6 Dirncs in Molcular Markrs bwn Coliis-associad

Colorcal Cancr wih or wihou Primary Sclrosing Cholangiis

and Sporadic Colorcal Cancr

73

Chapr 7 Mhylaion Prols o Sporadic and Coliis-associad Colorcal

Cancr

89

Chapr 8 Wn-pahway Acivaion in IBD-associad Colorcal

Carcinognsis: Ponial Biomarkrs or Colonic Survillanc

103

Chapr 9 Summary and discussion 117

Ndrlands Samnvaing 123

Acknowldgmns 129

Abou h auhor 131



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CHaPter 1

Gnral inroducion



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8 |CHAPteR 1

Background

Infammaory bowl disas (IBD), comprising ulcraiv coliis (UC) and Crohns

disas (CD), is a chronic infammaory disordr o h gasroinsinal rac

characrizd by a rlapsing cours. Pains wih IBD ar a an incrasd risk o

dvloping colorcal cancr (CRC). eadn al. has shown cumulaiv risks o 2%,

8% and 18% ar 10, 20, and 30 yars o disas duraion, rspcivly 1. A mor

rcn ma-analysis, which cnsord or colcomy ra and criically appraisd

isolad small bowl Crohns disas and sudy populaion, rpord cumulaiv

CRC risks o 1%, 2%, and 5% ar 10, 20 yars, or mor han 20 yars in all IBD

pains in populaion-basd sudis. In rrral-cnr sudis and in pains wih

an IBD diagnosis bor h hird dcad, his risk was signicanly incrasd

(Lugns al., unpublishd rsuls). Alhough IBD-rlad CRC only consius

1-2% o all CRCs, i is a rqun caus o dah in his young pain group and IBD

rmains on o h hr high-risk condiions or dvloping CRC along wih amilial

adnomaous polyposis and Lynch syndrom. Risk acors or IBD-rlad CRC ar,

among ohrs, disas duraion, concomian primary sclrosing cholangiis, posiiv

amily hisory, xn o h disas and svriy o infammaion 2,3. ths and

ohr risk acors or IBD-rlad CRC ar urhr dscribd in a rviw shown in

Chp 2.

Pimy Sclosing CholngiisAn idnid risk acor or CRC in pains wih IBD is concurrn primary sclrosing

cholangiis (PSC). PSC is a chronic cholsaic livr disas, characrizd by

infammaion and brosis o h inra- and xra hpaic bil ducs 4. th pahognsis

and aiology ar unknown and a ramn o sop or rvrs h progrssion o

h disas is no availabl. Apar rom h dvlopmn o dcompnsad livr

cirrhosis wih ransplanaion as h only civ ramn, li xpcancy o

PSC pains is sriously hrand by h incrasd risk o dvloping

cholangiocarcinoma (CCA) and CRC. In h liraur, conradicory rsuls ar

rpord on h risk o CCA and CRC in his subgroup o IBD pains5-7

. thror,w drmind h risk o malignancis in a larg cohor o Duch PSC pains

(Chp 3).

In Chp 4, w compard pains wih IBD-rlad CRC and concurrn PSC o

pains wih IBD-rlad CRC alon wihou involvmn o h biliary rac wih

rspc o clinical characrisics, ndoscopic and hisological ndings, and prognosis.

th rsuls could ponially hlp dning improvd clinical managmn sragis

or individuals wih IBD and concurrn PSC and guid uur rsarch in

pahoysiological mchanisms in PSC-IBD-rlad CRC.



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9Inroducion |

Phognsis

Coliis-associad CRC dvlops hrough h so-calld infammaion-dysplasia-

carcinoma squnc insad o h adnoma-carcinoma squnc in sporadic CRC

8. Infammaion plays an imporan rol in h dvlopmn o cancr rsuling in a

high urnovr o clls and an incrasd producion o DNA-damaging agns 9. th

gradual accumulaion o (pi) gnic alraions causs damag o imporan cllular

procsss lading o ransormaion o normal mucosa o low-grad dysplasia (LGD),

which may progrss o high-grad dysplasia (HGD) and vnually o invasivnss.

In h sporadic as wll as h coliis-associad carcinognic pahway h sam

gn alraions ar involvd, only h iming and rquncy o h muaions sm

o dir (Figur 1).

Apar rom h wo major pahways o gnic insabiliy, i.., h chromosomal

insabiliy pahway (CIN) and h microsalli insabiliy pahway (MSI), pignic

alraions such as hyprmhylaion hav also bn shown o play a major rol in

carcinognsis. th rm DNA mhylaion dscribs h addiion o a mhyl group

o h cyokin bas o DNA. exnsiv mhylaion o cyosin bass is associad

wih promor silncing rsuling in a modicaion in gn xprssion. In his way,

Figu 1. Comparison bwn sporadic colon cancr and coliis-associad colon cancr



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10 |CHAPteR 1

hyprmhylaion causs silncing o mulipl (umour supprssor) gns and

conribus o cancr iniiaion and progrssion 10. Chaprs 5 -8 rpors on molcular

aspcs o carcinognsis in IBD-rlad CRC.

Chaper 5 ocuss on h molcular background o colorcal umours in IBD wih

concurrn PSC. Microsalli saus was assssd in hs umours and compard

o ohr subgroups o CRC, such as sporadic CRC, Lynch syndrom-rlad CRC and

IBD-rlad CRC. th molcular background o PSC-IBD-rlad CRC was urhr

lucidad in Chaper 6 by immunohisochmical xprssion and muaion-analysis o

gns involvd in carcinognsis. In chaper 7 h mhylaion saus o svral umour

supprssor gns was assssd in infammaion-rlad CRC and non-infammaion-

rlad CRC. Involvmn o an imporan carcinognic pahway, h Wn-pahway,

in infammaion-rlad colorcal carcinognsis was valuad in chaper 8.

Suvillnc

th muli-sp characr o carcinognsis in IBD maks his chronic disordr suiabl

or survillanc wih h ulima goal o dc noplasia a a pr-cancrous sag

or a las a a mor avourabl sag or prorming a curaiv ramn. th

guidlins, dnd by h Amrican Gasroinsinal Associaion (AGA) and h

Briish Sociy or Gasronrology (BSG) rcommnd scrning colonoscopy ar

8 yars o disas duraion in xnsiv IBD, comprising h whol colorcum

ollowd by survillanc wihin 1-2 yars ar scrning colonoscopy 3. Survillancrcommndaions in pains wih IBD and concomian PSC ar o iniia

survillanc immdialy ar h diagnosis PSC by prorming colonoscopy a a

yarly basis. Howvr, no clinical vidnc is availabl o suppor hs

rcommndaions. Lundquis al hav shown ha coliis on runs a mor

quiscn cours in PSC-IBD pains han in UC pains wihou PSC 11. Furhrmor,

hisological ndings o coliis may prcd clinical sympoms by as much as 7 yars,

which maks i mor dicul o drmin h xac duraion o IBD 12.

Svral drawbacks o ndoscopic survillanc hav impdd is accpanc asa common pracic prormd by gasronrologiss on a worldwid basis.

ths includ inrobsrvr variabiliy among pahologiss whn grading

dysplasia and h disapparanc o dysplasia on rpa biopsy ar prviously

conrmd dysplasia 13,14. I his is combind wih h rquirmn o ak a las 33

random biopsis o rul ou dysplasia wih 90% crainy, his has ld o considrabl

dba on h cacy and h bns o colonoscopic survillanc 15. In addiion,

h im- and cos-consuming cs as wll as h burdn o pains o undrgo

invasiv ndoscopy a rgular inrvals ar imporan limiaions o survillanc.

Finally, i is sill unclar whhr colcomy should b advisd o pains wih LGD



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11Inroducion |

ound in biopsis akn during survillanc ndoscopy. th main rason or his is

ha h risk o progrssion o LGD o HGD or vn adnocarcinoma is sill subjc

o dba. Svral rpors sudying h adhrnc o gasronrologiss o h

inrnaional guidlins rval a low adhrnc o hs proocols, probably du o

h abov mniond rasons 16,17.

Dspi all h scpicism, dysplasia has bn unmisakably idnid as a srong

prdicor o CRC in IBD pains and vidnc o improvd survival or pains

who undrwn survillanc is mrging. HGD is gnrally considrd o b an

indicaion or colcomy du o h high risk o synchronous or machronous

CRC 18. th progrssion ra o LGD howvr has or a long im provokd mor

conrovrsy han HGD as an indicaion or prococolcomy. A randomizd conrolld

rial would b h idal sudy dsign o assss whhr survillanc rally rducs

IBD-CRC-rlad moraliy. to da, such rial has no bn conducd mainly

bcaus a vry larg populaion is ndd and ollow-up o his cohor should b

don or a long priod, i.., a las 5-10 yars. Cas-conrol sudis provid a mor

accssibl insigh. Fw sudis hav assssd h qusion whhr survillanc

programs rduc CRC-rlad moraliy 19-21. All publicaions so ar poin owards a

bncial c o survillanc, wih mor avourabl umour sags bing dcd

in pains includd in a survillanc program.

th mos prdominan limiaions o h survillanc guidlins includ samplingrror a h im o biopsy, inrobsrvr disagrmn in hisologically grading o

dysplasia, i.., LGD and disagrmn on h opimal managmn o LGD, bing

ihr survillanc or colcomy. this indicas h nd or coninud rsarch

ino h molcular pahognsis o IBD-associad CRC, wih h hop ha nally

args or prvnion will b idnid. A mor pain-ailord approach in

survillanc is absoluly ssnial o kp such a programm cos-civ bu

also o kp h burdn o pains as low as possibl.

Svral sudis hav rid o unravl h molcular background o coliis-associad

CRC in ordr o dc biomarkrs ha may indica progrssion rom normal opr-noplasic mucosa. ths biomarkrs in combinaion wih advancd ndoscopic

chniqus, aiming a br visualizing arly sag CRC in IBD (dysplasia and arly

adnocarcinoma), may add o a mor cin and opimal survillanc program.

Individual survillanc programs may incras pain car in svral ways and

vnually improv survival.

th gnral and ovrall aim o his hsis is hror o conribu o h lucidaion

o coliis-associad carcinognsis, vnually lading o a mor opimizd

survillanc program or pains wih longsanding IBD and a risk o dvloping

CRC.



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12 |CHAPteR 1

Rrnc Lis

1. eadn JA, Abrams KR, Maybrry JF. th risk o colorcal cancr in ulcraiv coliis: a ma-analysis.

Gu 2001;48:526-535.2. Farray FA, Odz RD, eadn J, Izkowiz SH, McCab RP, Dassopoulos t, Lwis JD, Ullman tA,

Jams t, III, McLod R, Burgar LJ, Alln J, Brill JV. AGA mdical posiion samn on h diagnosis

and managmn o colorcal noplasia in infammaory bowl disas. Gasronrology

2010;138:738-745.

3. Farray FA, Odz RD, eadn J, Izkowiz SH. AGA chnical rviw on h diagnosis and managmn

o colorcal noplasia in infammaory bowl disas. Gasronrology 2010;138:746-74, 774.

4. Chapman RW, Arborgh BA, Rhods JM, Summrld JA, Dick R, Schur PJ, Shrlock S. Primary

sclrosing cholangiis: a rviw o is clinical aurs, cholangiography, and hpaic hisology. Gu

1980;21:870-877.

5. Broom U, Lobrg R, Vrss B, eriksson LS. Primary sclrosing cholangiis and ulcraiv coliis:

vidnc or incrasd noplasic ponial. Hpaology 1995;22:1404-1408.

6. Gurbuz AK, Giardillo FM, Baylss tM. Colorcal noplasia in pains wih ulcraiv coliis andprimary sclrosing cholangiis. Dis Colon Rcum 1995;38:37-41.

7. Lous eV, Jr., Sandborn WJ, trmain WJ, Mahony DW, Zinsmisr AR, Oord KP, Mlon LJ, III.

Risk o colorcal noplasia in pains wih primary sclrosing cholangiis. Gasronrology

1996;110:432-440.

8. Izkowiz SH, Yio X. Infammaion and cancr IV. Colorcal cancr in infammaory bowl disas:

h rol o infammaion. Am J Physiol Gasroins Livr Physiol 2004;287:G7-17.

9. trzic J, Grivnnikov S, Karin e, Karin M. Infammaion and colon cancr. Gasronrology

2010;138:2101-2114.

10. Jass JR, Whihall VL, Young J, Lgg BA. emrging concps in colorcal noplasia.

Gasronrology 2002;123:862-876.

11. Lundqvis K, Broom U. Dirncs in colonic disas aciviy in pains wih ulcraiv coliis wih and

wihou primary sclrosing cholangiis: a cas conrol sudy. Dis Colon Rcum 1997;40:451-456.12. Broom U, Lobrg R, Lundqvis K, Vrss B. Subclinical im span o infammaory bowl disas

in pains wih primary sclrosing cholangiis. Dis Colon Rcum 1995;38:1301-1305.

13. Bris R, Ljung t, Jaramillo e, Rubio C. Low-grad dysplasia in xnsiv, long-sanding infammaory

bowl disas: a ollow-up sudy. Dis Colon Rcum 2002;45:615-620.

14. eadn J, Abrams K, McKay H, Dnly H, Maybrry J. Inr-obsrvr variaion bwn gnral and

spcialis gasroinsinal pahologiss whn grading dysplasia in ulcraiv coliis. J Pahol

2001;194:152-157.

15. Rubin Ce, Haggi RC, Burmr GC, Brnnall tA, Svns AC, Lvin DS, Dan PJ, Kimmy M, Prra

DR, Rabinovich PS. DNA anuploidy in colonic biopsis prdics uur dvlopmn o dysplasia in

ulcraiv coliis. Gasronrology 1992;103:1611-1620.

16. eadn JA, Ward BA, Maybrry JF. How gasronrologiss scrn or colonic cancr in ulcraiv

coliis: an analysis o prormanc. Gasroins endosc 2000;51:123-128.17. van Rijn AF, Fockns P, Sirsma PD, Oldnburg B. Adhrnc o survillanc guidlins or dysplasia

and colorcal carcinoma in ulcraiv and Crohns coliis pains in h Nhrlands. World J

Gasronrol 2009;15:226-230.

18. Brnsin CN, Shanahan F, Winsin WM. Ar w lling pains h ruh abou survillanc

colonoscopy in ulcraiv coliis? Lanc 1994;343:71-74.

19. Choi PM, Nugn FW, Schoz DJ, Jr., Silvrman ML, Haggi RC. Colonoscopic survillanc rducs

moraliy rom colorcal cancr in ulcraiv coliis. Gasronrology 1993;105:418-424.

20. Lashnr BA, Kan SV, Hanaur SB. Colon cancr survillanc in chronic ulcraiv coliis: hisorical

cohor sudy. Am J Gasronrol 1990;85:1083-1087.



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13Inroducion |

21. Lugns MW, Oldnburg B, Sirsma PD, van Bodgravn AA, Dijksra G, Homms DW, d Jong

DJ, Sokkrs PC, van dr Woud CJ, Vlggaar FP. Colonoscopic survillanc improvs survival ar

colorcal cancr diagnosis in infammaory bowl disas. Br J Cancr 2009;101:1671-1675.



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14 |



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MMH Classn, PD Sirsma, FP Vlggaar

Dparmn o Gasronrology and Hpaology, Univrsiy Mdical Cnr Urch

in press: Best Practice & Research: Clinical Gastroenterology

IBD-rlad carcinoma and lymphoma

CHaPter 2



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16 |CHAPteR 2

Absrac

Pains wih infammaory bowl disas (IBD) hav an incrasd risk o dvloping

colorcal cancr (CRC). Risk acors ar xn and svriy o colonic infammaion,

concurrn primary sclrosing cholangiis, and a posiiv amily hisory o sporadic

CRC. th chromosomal insabiliy, microsalli insabiliy and hyprmhylaion

pahways orm h molcular background o IBD-rlad carcinognsis, which is

no dirn rom sporadic CRC. th dysplasia-carcinoma squnc o IBD-rlad

colorcal carcinognsis maks pains suiabl or ndoscopic survillanc. In

h uur, nw molcular biomarkrs and ndoscopic chniqus may improv arly

dcion o prcursor lsions o IBD-rlad CRC. th ponial o aminosalicylas

and ursodoxycholic acid as chmoprvniv agns nds o b sudid in

randomizd clinical rials. Pains wih IBD who ar bing rad wih hiopurins

hav a slighly incrasd risk o dvloping lymphoproliraiv disordrs, whras

pains wih small bowl Crohns disas hav a high rlaiv risk and a small

absolu risk o dvloping small bowl adnocarcinoma.



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17IBD-rlad malignancis |

Inroducion

Pains wih infammaory bowl disas (IBD), i.. Crohns disas (CD) or

ulcraiv coliis (UC), hav chronic rlapsing infammaion o h colon, and in cas

o CD, also o h small bowl. In 1925, Crohn and Rosnbrg wr h rs o rpor

an associaion bwn IBD and colorcal carcinoma (CRC). Sinc hn, i has

bcom clar ha pains wih IBD locad in h colon ar a an incrasd risk o

dvloping CRC. Alhough IBD-rlad CRC only consius 1-2% o all CRCs, i is

a rqun caus o dah in his rlaivly young pain group and rmains on o

h hr high-risk condiions or dvloping CRC along wih amilial adnomaous

polyposis (FAP) and Lynch syndrom. th dysplasia-carcinoma squnc o IBD-

rlad colorcal carcinognsis maks pains suiabl or ndoscopic survillanc.

Updad survillanc guidlins rom h Amrican Gasronrological Associaion

(AGA) and Briish Sociy or Gasronrology (BSG) hav rcnly bn publishd

(tabl 1) 1,2. Lymphoma and small bowl adnocarcinoma ar ohr IBD-rlad

malignancis ha may occur in his group o pains.

risk o dvloping CrC

th magniud o CRC risk in IBD rmains a opic o dba. A landmark sudy on

h risk o CRC in IBD pains is h ma-analysis o eadn al. prormd in

2001, showing risks o 2%, 8% and 18% ar 10, 20, and 30 yars o disas,

rspcivly 3. ths rsuls wr basd on sudis wih highly variabl mhodologisor inclusion criria and hror nd o b inrprd wih cauion. Sinc 2001,

svral populaion-basd sudis hav bn publishd indicaing lowr han

prviously assumd risks. Brnsin al. calculad incidnc ra raios (IRR) or

CRC in IBD pains machd wih a non-IBD populaion and ound an IRR o 2.64

(95%CI 1.69-4.12) in CD pains and 2.75 (95%CI 1.91-3.97) in UC pains 4. A

rcn sudy rom easrn europ showd cumulaiv risks o 0.6%, 5.4%, and

7.5% ar a disas duraion o 10, 20, and 30 yars, rspcivly 5. ths sudis

also showd a dcras in CRC incidnc ovr im. Spculaions on h rasons

or his dclin includ h us o mainnanc hrapy wih possibl chmoprvnivc, highr clinical awarnss o prcursor lsions, mor wid-sprad pracic o

ndoscopic survillanc, and a mor aggrssiv surgical approach owards

dysplasia.

risk cos o CrC

Svral risk acors or IBD-rlad CRC hav bn idnid. Firs, disease duraion

was ound o b an imporan risk acor. I is howvr dicul o drmin h

xac commncmn o IBD in individual pains. eadn al. rpord a cumulaiv

risk o only 2% ar 10 yars o UC 3. I is imporan o ralis ha som sudis



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18 |CHAPteR 2

includd in his ma-analysis xcludd all pains wih CRC occurring wihin h

rs dcad o IBD. Morovr, Lugns al. rpord ha 17-28% o IBD-rlad

CRCs occur in h rs dcad ar diagnosing IBD 6. thror, on may qusion

whhr duraion o IBD is imporan or valuaing h risk o CRC in individual

pains.

A scond risk acor is h exen of coliis. An incrasing gradin in CRC risk has

bn rpord in IBD pains wih xn o coliis ranging rom prociis o l-

sidd coliis o pancoliis, showing rlaiv risks o 1.7, 2.8, and 14.8, rspcivly.

Similar rsuls hav bn rpord in anohr sudy wih rlaiv risks o 19.2 and

2.8 or pains wih pancoliis and l-sidd disas, rspcivly 7,8. I is dicul

o compar sudis du o dirn dniions o colonic involvmn and variousmhods ha hav bn usd o ascrain disas xn, varying rom barium

nma sudis o ndoscopic or hisopahological chniqus. Microscopic changs

ar suprior in dning disas xn compard o ndoscopic or radiographic

changs, bcaus noplasia may aris in aras wihou ndoscopic vidnc o

infammaion 9. Backwash iliis, dnd as involvmn o h ilum in UC pains,

has also bn suggsd as a risk acor or CRC. Howvr, a mor rcn sudy

wih sric inclusion criria (no CD pains) rpord no incrasd risk in pains

wih backwash iliis 10 .

Sviy o inlmmion may also add o an incrasd risk. earlir sudis mayno hav rcognizd svriy o infammaion as risk acor bcaus pains wih

svr infammaion usd o undrgo colcomy a an arly sag. Furhrmor,

svriy o infammaion may b an unrliabl variabl o assss in rrospciv

sudis. Mor rcn daa did show ha svriy o infammaion is an indpndn

risk acor. Rur al. rpord a posiiv associaion bwn svriy o

infammaion and h dvlopmn o CRC (OR 4.6 95%CI 2.1-10.5), lar conrmd

by Gupa al. (OR 3.0 95%CI 1.4-6.3) 11,12. Rcn AGA survillanc guidlins hav

bn adjusd accordingly and survillanc a mor rqun inrvals is now advisd

in pains wih svr infammaion.

tbl 1. Summary o AGA Guidlins 2010.

I. Scrning colonoscopy 8 yars ar ons o sympoms

II. L-sidd/xnsiv coliis: sar survillanc wihin 2 yars ar iniial scrning

III. Rpa survillanc vry 1-3 yars

IV. Biopsis should b akn o ach anaomic scion o h colon

V. Pains wih PSC: sar annual survillanc ar his diagnosis

VI. Idally, survillanc colonoscopy should b prormd whn rmission is achivd

VII. A posiiv amily hisory in rs-dgr rlaivs, ongoing aciv infammaion, anaomic

abnormaliis, or mulipl infammaory psudopolyps may bn rom mor rqun

survillanc colonoscopis



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A ourh risk acor is concurrn primary sclerosing cholangiis (PSC) 13,14. A rcn

Duch PSC cohor sudy ound 10-yar and 20-yar CRC risks o 14% and 31%,

rspcivly 15. Rmarkably, wo-hird o PSC-rlad CRCs wr locad in h

proximal par o h colon 16. A ma-analysis by Soikno al. rpord a our-old

highr risk o CRC in pains wih concurrn PSC compard o pains wih IBD

alon 17. thr is no clar xplanaion or his addiional risk; coliis-rlad as wll

as PSC-rlad acors may b rsponsibl. Guidlins advic o sar annual

survillanc or his spcic subgroup dircly ar diagnosing PSC.

A posiiv mily hisoy o CrC impars a wo-old incrasd risk o CRC in IBD

pains. A sudy by Askling al. showd ha almos 10% o all CRC cass occurrd

in IBD pains wih a posiiv amily hisory or CRC 18. Morovr, a posiiv amily

hisory or CRC was rpord o b wic as common in UC-CRC pains compard

o UC conrols machd or xn and duraion o coliis 19. th risk o CRC in

rlaivs o IBD pains wihou CRC was no incrasd; howvr, rs-dgr

rlaivs o pains wih IBD-rlad CRC naild an 80% incrasd risk o

dvloping CRC 20.

Anohr risk acor may b young age a onse of IBD. ekdom al. rpord a

cumulaiv risk o 40% ar 35 yars o disas in pains diagnosd bor h ag

o 15 yars and 25% in pains diagnosd wih IBD bwn 15-39 yars o ag 7. In

conras, Grnsin al. showd an ag-spcic CRC incidnc o 3.6 pr 1,000

pain yars in pains who wr 10-19 yars old a ons o IBD and 12.7 in pains

who wr bwn 30-39 yars old a ons 21. I is imporan o ralis ha disasduraion and a low risk o CRC a young ag in h gnral populaion may b major

conoundrs. Rcn guidlins conclud ha pains wih IBD ons a arly ag

hav h sam CRC risk as in aduls wih disas ons a oldr ag, rsuling in h

advic o prorm rgular survillanc ndoscopis also in his pain group.

Dysplsi

Dysplasia is h only currnly availabl (hisological) markr associad wih

progrssion o CRC. Dysplasia is dnd as noplasic alraions o h pihlium

wihou invasivnss ino h lamina propria. th diagnosis o dysplasia is dividdino 3 subgroups: (a) ngaiv or dysplasia, (b) indni or dysplasia (IND), and (c)

posiiv or dysplasia, urhr subdividd ino low-grad (LGD) and high-grad (HGD)

dysplasia 22.

th inra- and inr-obsrvr agrmn o diagnosing dysplasia among pahologiss

is low, spcially in disinguishing LGD rom IND or raciv mucosa 23. thror,

guidlins rcommnd ha biopsis showing dysplasia should b rviwd by an

xprincd gasroinsinal pahologis.

Svral sudis hav rpord a posiiv c o ndoscopic survillanc on survival

o IBD pains 24-27. Lugns al. dmonsrad in 149 pains wih IBD-rlad



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20 |CHAPteR 2

CRC a signican rducion in CRC-rlad moraliy in h survillanc group

compard o h non-survillanc group (5-yar survival ra o 100% and 74%,

rspcivly). Morovr, a signicanly highr proporion o arly-sag umours was

ound in h survillanc group. th oucoms o h abov-mniond sudis nd

o b inrprd wih cauion bcaus o non-randomizd dsigns.

Dysplasic lsions may dir in apparanc varying rom fa o raisd and rom

uniocal o muliocal 22. As lsions ar no always visibl during ndoscopy, Rubin

al. calculad ha i is ncssary o ak a las 33 random biopsis, in ordr o

dc dysplasia wih 90% condnc 28.

th dcion o dysplasia can b improvd wih nw ndoscopic chniqus, such

as spraying h colonic mucosa wih mhyln blu or indigo carmin

(chromondoscopy). this chniqu incrass snsiiviy and spciciy o ndoscopic

survillanc and qusions h nd or random biopsis. Kisslich al. randomizd

pains o convnional colonoscopy or chromondoscopy using mhyln blu.

th ra o ndoscopically dcd dysplasia was signicanly highr wih mhyln

blu spraying compard o convnional ndoscopy alon (32 vs 10 biopsis wih

noplasia) 29. Similar rsuls wih chromondoscopy hav bn rpord by Marion

al. wih 17 noplasic lsions bing dcd wih argd chromondoscopy

compard o 3 lsions wih random biopsis alon and 9 lsions wih argd

biopsis using convnional colonoscopy 30. Anohr sudy rpord an addiional

dcion o 114 abnormaliis in 55 pains, o which 7 wr dysplasic, using

indigo carmin spraying ar convnional colonoscopy had alrady bnprormd 31. Consqunly, h rcnly rvisd Briish Sociy or Gasronrology

(BSG) guidlins srongly adviss using chromondoscopy or survillanc in IBD.

A rcn sudy usd a mahmaical modl o compar h snsiiviy o random

biopsy survillanc wih ha o nhancd ndoscopy (or xampl chromondoscopy),

which can dc dysplasic lds o jus 10 mm in diamr. Calculaions showd

ha sandard survillanc was insnsiiv o dc small aras o dysplasia. th

numbr o random biopsis ndd o achiv comparabl snsiiviy as wih

nhancd ndoscopy was vry high (n=4690). th clinical implicaions o dcing

such small dysplasic lds, howvr, ar unknown, paricularly bcaus hprogrssion risk is unknown. Improvmn o dcion dos no ncssarily lad

o an improvd oucom. Morovr, i could lad o ovr-diagnosis, an incrasd

numbr o ndoscopic inrvnions or colcomis, rsuling in addiional morbidiy

and vn moraliy 32.

I is imporan o considr h clinical consquncs o diagnosing dysplasia.

Brnsin al. rpord ha 32% o pains wih HGD progrssd o CRC during

ollow-up. Furhrmor, as HGD has bn associad wih a high ra o synchronous

CRCs (42%), prococolcomy is rcommndd in hs pains. For hos wih

LGD, h probabiliy o vnually progrssing was 16-29% 33. Connll al. rpord



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a 5-yar progrssion ra rom LGD o HGD or CRC o 54%, which is similar o ha

rpord by anohr group 34,35. A mor rcn sudy invsigad fa LGD, rviwd

by 3 xprincd gasroinsinal pahologiss and showd a 5-yar progrssion risk

o 37% 36. this wid rang o progrssion ras probably rfcs h larg inr-

obsrvr disagrmn among pahologiss. th 5-yar progrssion risk or IND has

bn rpord o vary bwn 5-28% 33,36. Du o h variabiliy in progrssion ras,

i is no clar wha h hrapuic implicaions or a diagnosis o LGD ar. In

paricular or uniocal dysplasia dcd wih random biopsis i is unclar wha o

advis h pain. In our xprinc, nhancd survillanc sms o b sa. I is

suggsd o considr all clinical, ndoscopic, and hisological risk acors and discuss

hs xnsivly wih h pain bor making h dcision o prorm ihr

colcomy or nhancd survillanc. Figur 1 shows a fow char o h managmn

o dysplasia basd on currn guidlins.

th im- and cos-consuming cs, h low inr-obsrvr hisological agrmns

as wll as h uncrain progrssion ra o LGD srss h imporanc o idniying

ohr acors ha rliably idniy pains a risk. Br undrsanding o h

molcular carcinognsis in an nvironmn o chronic infammaion may provid

molcular markrs ha could idniy pains a risk or noplasic progrssion.

this could rsul in a mor pain-ailord approach wih individual risk sraicaion

and adjusd survillanc inrvals.

Figu 1. Flow char o h managmn o dysplasia basd on currn guidlins



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22 |CHAPteR 2

IBD-ld ccinognsis

I is known ha IBD-rlad CRC dvlops hrough h so-calld infammaion-

dysplasia-carcinoma squnc insad o h sporadic adnoma-carcinoma

squnc 37. Infammaion plays an imporan rol in h iniiaion and dvlopmn

o CRC 38. th gradual accumulaion o (pi)gnic alraions causs damag o

imporan cllular procsss lading o ransormaion ino LGD/HGD, which may

progrss o invasiv CRC.

Som aurs o h IBD-rlad molcular colorcal carcinognsis ar qual and

som dir rom is sporadic counrpar. th majoriy (85%) o sporadic CRCs

ariss du o problms in chromosomal sabiliy and sgrgaion, rsuling in gain

or loss o chromosoms, known as h chromosomal insabiliy pahway (CIN). two

ky umour supprssor gns involvd in his pahway ar adnomaous polyposis

coli (APC) and p53. th iming and rquncy o muaions in APCand p53sm o

dir bwn sporadic and IBD-rlad carcinognsis. th scond main

carcinognic pahway is h microsalli insabiliy pahway (MSI), which involvs

loss o uncion o on o h mismach rpair (MMR) gns ihr by muaion or

hyprmhylaion o h MLH1 promor rgion. Abou 15% o h sporadic umours

dvlop hrough his pahway, in paricular righ-sidd umours. th sam disribuion

o CIN and MSI is also ound in IBD-rlad CRCs 37. Apar rom h wo major

pahways o gnic insabiliy, pignic alraions such as hyprmhylaion,

lading o h addiion o a mhyl group o h cyokin bas o DNA, hav also

bn shown o play a rol in carcinognsis. Hyprmhylaion may caus silncingo mulipl gns and conribus o cancr iniiaion and progrssion 38.

Chomosoml insbiliy phwy

Aneuploidy

Anuploidy (abnormal DNA conn) has bn sudid or svral dcads and has

bn shown o b an arly vn, vn prcding dysplasia 28,39. I is on o h w

markrs ha has bn sudid longiudinally. Lobrg al. hav shown ha

anuploidy may also occur simulanously wih h dvlopmn o dysplasia or

vn hrar40

. Furhrmor, CRCs may also dvlop wihou h dvlopmno anuploidy 41. So, alhough anuploidy may hav addiional valu in cancr

survillanc indicaing a high risk o progrssion o noplasia, i canno b usd as

soliary markr o noplasic progrssion.

P53

th p53 proin arrss h nry o clls wih DNA damag ino h S phas, hrby

providing an opporuniy or DNA rpair o procd hrough normal rpair mchanisms,

whras i riggrs apoposis in clls in which DNA damag is irrvrsibl. Loss o

hs prociv mchanisms prdisposs o malignancy, spcially undr condiions



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o prsisn pihlial injury and high cll urnovr, such as hos prvailing in

coliis 42. Mos o h p53muaions ar missns muaions, producing an alrd

proin ha accumulas in h cll nuclus which can b dmonsrad by

immunohisochmisry 43. Immunohisochmical xprssion, howvr, is an indirc

manisaion o p53 inacivaion. Som muaions, h so-calld null-muaions, do

no rsul in dcabl xprssion o p53 proin. thror, in cas o a compl

ngaiv immunohisochmical xprssion, p53 muaion analysis should b

prormd.

Svral sudis hav shown ha alraions in p53sm o rprsn an arly vn

in IBD-rlad noplasia 44,45. Pains wih longsanding UC wihou noplasia and

showing p53 xprssion dvlop up o 5 ims mor likly noplasia han hos

wihou 46. Similarly, Holzmann al. rpord a highr rquncy o p53muaions

in non-noplasic pihlium in pains wih noplasia han hos wihou

noplasia 47. Howvr, a rcn immunohisochmisry sudy did no rpor an arly

rol or p53 xprssion, which was ound only in alrady noplasic mucosa 48.

exprssion o p53 may b usul as a markr o disinguish bwn LGD and

rgnraiv infamd mucosa, alhough p53 xprssion also has bn rpord o

b associad wih infammaion. Howvr, a sudy by Wong al showd ha a

srong innsiy o p53 saining was only ound in dysplasic lsions 49.

Wnt-pathway

th -catenin mdiad Wn-pahway conrols proliraion and dirniaion in hcolonic sm cll comparmn and is involvd in carcinognsis 50. Loss o APC

uncion rsuls in acivaion o ranscripion o arg gns such as C-mycand

Cyclin D1. In gnral, Wn-pahway acivaion dominas arly sporadic

carcinognsis, whras Wn acivaion occurs lss rqunly, and, i occurring,

usually a a la sag o IBD-rlad carcinognsis 51. W rcnly rpord,

howvr, arly and rqun Wn acivaion in IBD-rlad noplasia, basd on nuclar

-canin and Cyclin D1 immunohisochmical saining. exprssion o hs markrs

was ound in 50% o non-dysplasic mucosa rom IBD pains wih colonic noplasia

lswhr48

. Van Dkkn al. also ound incrasd nuclo-cyoplasmic -caninsaining in 88% and 79% o dysplasic and cancrous lsions, rspcivly, whras

ohr sudis hav shown a low rquncy o APCand -catenin muaions in IBD-

rlad CRC compard o sporadic CRC 52,53. Hnc, availabl daa on h rol o Wn

acivaion in IBD-rlad carcinognsis sm o b conficing. Acivaion o h

Wn-pahway in arly IBD-rlad carcinognsis sms o b causd by ohr gn

alraions han APCmuaions.



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24 |CHAPteR 2

Kras

Krasplays a pivoal rol in h ransmission o growh-promoing signals rom h

cll-surac o h nuclus and is assumd o b an arly vn in sporadic

carcinognsis. A low incidnc o Krasmuaions in IBD-rlad umours (0-15%)

compard wih sporadic umours (75%) has bn rpord and may indica a minor

rol or his oncogn 54. Anohr xplanaion or h low incidnc o Krasmuaions

in coliis-associad CRCs may b h occurrnc o alraions in ohr Ras

associad gns 55.

DNA fngerprinting

DNA ngrprining is a chniqu ha uss random primrs o ampliy h gnom

and o dc widsprad gnic insabiliy (alllic imbalancs). Chn al. hav

rpord an incrasd gnomic insabiliy in adjacn hisologically normal mucosa

o IBD pains wih noplasia. Mor imporanly, i was no ound in colonic mucosa

o pains wihou noplasia or in non-UC conrols 56. Furhr sudis ar ndd

o drmin is ponial rol in biomarkr-basd survillanc.

Micoslli insbiliy phwy

th rol o h DNA MisMach Rpair (MMR) sysm is o mainain gnomic ingriy

by corrcing mismachs ha ar gnrad by rrors in bas pairing occurring

during normal DNA rplicaion. Inacivaion o MMR gns causs gnomic insabiliy,

lading o a spcic phnoyp known as microsalli insabiliy (MSI). Abou 15-20% o sporadic CRCs show MSI, wih a high prvalnc in h proximal colon 57.

Insad o a grm lin muaion as in Lynch syndrom, MSI ariss in sporadic CRC

hrough hyprmhylaion o h promor rgion o hMLH1, on o h MMR gns,

causing ranscripional silncing 58.

th prvalnc o MSI-High saus in IBD-rlad CRCs varis bwn 9-15% 59-61,

rsuling in a similar disribuion as in sporadic CRCs. Schulmann al. did no nd

an associaion bwn MSI and clinical characrisics in IBD-rlad CRCs, such

as a proximal umour locaion, mal gndr, and a low umour dirniaion grad,

as has bn rpord in sporadic umours62

. A MSI-low phnoyp has bn rpordin non-noplasic acivly infamd mucosa o IBD pains 63. Som hav hypohsizd

ha h amoun o DNA damag causd by oxidaiv srss accompanid by chronic

infammaion may ovrwhlm h DNA MMR sysms abiliy o rpair small

alraions, wih as consqunc a MSI-low saus. In viro sudis hav suppord

his hypohsis 64. th clinical signicanc o his nding is y o b drmind.

CpG islnd mhylion phwy

Abrran mhylaion o promor rgion CpG islands is associad wih

ranscripional inacivaion o umour supprssor gns. In normal colorcal



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pihlium, incrasd mhylaion has bn ound wih aging, which is known as

ag-rlad mhylaion 65.

Alhough mhylaion has bn rpord o b associad wih infammaion, w

ound lss rqun mhylaion in IBD-rlad CRC compard o sporadic CRC 66.

Similar rsuls hav bn rpord by Konishi al. who compard mhylaion

lvls in dysplasic and umour sampls o IBD pains wih sporadic CRC umour

sampls 67. thy ound a highr mhylaion lvl in sporadic CRC compard o

IBD-rlad CRC. Mor imporanly, a highr dgr o mhylaion was dcd

in IBD-rlad dysplasia compard o IBD-rlad CRC sampls, suggsing ha

gnic changs and no pignic alraions largly drmin progrssion o

malignancy in infamd pihlium.

two yps o mhylaion hav bn rpord in h colon, i.. mhylaion saring

in normal mucosa as a uncion o ag (yp A) and mhylaion ha is rsricd o

umours (yp C). Issa al. invsigad h mhylaion saus o 5 gns in non-

dysplasic and dysplasic colonic mucosa o 23 IBD pains. Rmarkably, only

incrasd mhylaion lvls in yp A gns wr obsrvd, suggsing ha

carcinognsis may b a rsul o incrasd cll urnovr du o chronic

infammaion 68. Furhrmor, mhylaion was also ound in non-dysplasic mucosa

rom pains wih colorcal noplasia lswhr, implicaing ha ag-rlad

mhylaion marks a ld dc ha rfcs prdisposiion o colorcal noplasia.

In addiion, h daa suggs ha chronic infammaion is associad wih high lvls

o yp A mhylaion and ha coliis-rlad carcinognsis can b viwd as arsul o prmaur aging o colorcal pihlial clls.

A rcn sudy rpord incrasd mhylaion o som gns, i.. MINT1 and

RUNX3in non-adjacn normal mucosa o pains wih IBD-rlad CRC compard

wih UC conrols wihou CRC. ths rsuls suggs a possibl rol or mhylaion

as a scrning ool in cancr survillanc, hrby idniying hos a incrasd risk

o CRC in rouinly akn biopsis 69.

Chmopvnion

th us o pharmacohrapy as a chmoprvniv masur o rduc h risk odvloping CRC has bn sudid xnsivly. th ulima goal o chmoprvnion

is o rduc CRC risk, allowing or lss rqun survillanc xaminaions and a

rducion in incidnc o invasiv umours.

Aminosalicylates (5-ASA)

th mos widly sudid agn or chmoprvnion is 5-ASA. A ma-analysis o

nin obsrvaional sudis dmonsrad a rducd risk o dvloping CRC or

dysplasia wih 5-ASA wih an OR o 0.51 (95%CI 0.37-0.69) 70. this is in conras o

a rrospciv cas-conrol sudy in 25 pains wih IBD and CRC, ha ound no



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26 |CHAPteR 2

associaion bwn 5-ASA us and rducion in CRC risk 71. As conficing daa ar

availabl, h US Prvniv Srvics task Forc has concludd ha hr is

modra crainy ha h magniud o n bns is modra.

Ursodeoxycholic acid (UDCA)

UDCA has bn shown o signicanly rduc CRC risk in pains wih UC and

concurrn PSC. In animal sudis, UDCA was ound o inhibi colorcal

carcinognsis by rducing h colonic concnraion o scondary bil acids,

inhibiing rasgn muaions and by showing ani-oxidan aciviy 72. two spara

sudis hav also shown a chmoprvniv c o UDCA in IBD pains wih

concomian PSC, rsuling in a lowr incidnc o dysplasia (OR 0.18 and 0.26) 73,74.

thror, h us o UDCA in pains wih IBD and concurrn PSC is ncouragd;

howvr, h rol o UDCA as a chmoprvniv agn in UC wihou PSC is

unknown.

Immunomodulators and Biologicals

Us o azahioprin (AZA) or 6-mrcapopurin (6-MP) has no consisnly bn

shown o b associad wih lowr ras o CRC. Any possibl c o tNF

hrapy as chmoprvniv agn has no bn sudid y.

Folic acid, Calcium, Multivitamins & Corticosteroids

Folic acid dcincy has bn associad wih an incrasd risk o dvlopingCRC 75. Pains wih chronic IBD ar pron o ola dcincy du o inadqua

nuriional inak and rducd insinal absorpion. Svral sudis hav suggsd

a rnd owards procion agains CRC in ola usrs, alhough nihr sudy

dmonsrad saisical signicanc 76.

Oral or opical coricosroids, whil dmonsraing ani-noplasic cs in 2

sudis, ar associad wih signican sid cs and should no b usd as

chmoprvniv agns 77. Calcium, muliviamins, and sains hav no consisnly

bn associad wih lowr ras o CRC.

Lymphopoliiv disods in pins wih IBD

An incrasd risk o lymphoproliraiv disordrs (LD) in pains wih IBD has bn

a rpord in svral obsrvaional sudis 78,79. Howvr, populaion-basd sudis

did no conrm hs ndings. Askling al. did no nd an incrasd risk o LD in

50,000 Swdish IBD pains 80. Similar rsuls wr rpord by Lwis al. 81. On

larg populaion-basd sudy rom Canada howvr, rpord an incrasd risk o

LD in mal pains wih CD 4. Palli al. rom Ialy rpord an xcss risk o Hodgkin

lymphoma in pains wih IBD 82. ths rsuls hav no bn conrmd by

ohrs.



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th dvlopmn o LD may in ac b rlad o h us o immunosupprssivs

or h ramn o IBD or o h chronic cours o IBD isl. Rcn sudis hav

rpord a 5-old incrasd risk o dvloping LD undr AZA or 6-MP ramn 83.

th possibl rol o ani-tNF hrapy in having a rlaionship wih lymphomas is

dicul o drmin, mainly bcaus pains ar on co-rad wih hiopurins

or ohr immunosupprssans, such as sroids.

Smll bowl dnoccinom in CD

th risk o dvloping small bowl adnocarcinoma is incrasd in pains wih

CD wih a rlaiv risk o 28 compard o h gnral populaion. In pains wih

CD limid o h small bowl, h risk urhr incrass o 159 84. Palascak-Jui

al. dscribd cumulaiv risks o 0.2% a 10 yars and 2.2% a 25 yars in 1935 CD

pains wih small bowl involvmn a diagnosis 85.

Risk acors or small bowl adnocarcinoma in CD includ small bowl sricurs,

chronic sulous disas, CD locad in h disal jjunum and ilum, a small bowl

bypass loop, and immunosupprssiv hrapy wih AZA, 6-MP or ani-tNF

agns 86.

th carcinognsis o small bowl adnocarcinoma is sill unknown du o h poor

accssibiliy o h small bowl and h low ovrall incidnc. Svral hypohss

hav bn posulad o xplain h rducd absolu carcinoma risk including a

rapid ransi im lading o a shor xposur im o carcinognic subsancs, h

absnc o scondary bil acids in h small bowl, and larg quaniis o lymphoidissu prsn in h small bowl.

Survival is poor or pains wih small bowl adnocarcinoma wih rpord 5-yar

survival ras bwn 20-30%. Moraliy ar 1-2 yars varis bwn 30% and

60% 87. Unorunaly, our diagnosic ools o invsiga h small bowl ar currnly

no adqua o dc small bowl adnocarcinoma a an arly sag.

Summary

Pains wih IBD hav an incrasd risk o dvloping CRC, bu h magniud o

h risk dpnds on h yp o pain populaion sudid. Idnid risk acors

includ xn and svriy o disas, concurrn PSC and a posiiv amily hisory

or sporadic CRC. endoscopic survillanc improvs ovrall survival and dcrass

CRC-rlad moraliy, mos likly du o dcion o arly noplasic lsions wih a

mor avourabl prognosis. Dysplasia is currnly h only markr associad wih

progrssion o CRC. Pains wih HGD ar advisd o undrgo prococolcomy.

Clinical dcision making in pains wih LGD is impdd by h low inrobsrvr

agrmn among pahologiss and h wid variaion o obsrvd progrssion risks



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28 |CHAPteR 2

in LGD. Chromondoscopy wih mhyln blu or indigo carmin incrass snsiiviy

and spciciy o dysplasia dcion. th progrssion risk o small dysplasic lsions

dcd by nhancd ndoscopy is howvr, no known y. In h uur, biomarkrs

may aid in risk sraicaion and clinical managmn o pains wih IBD-rlad

CRC. Drugs, such as 5-ASA and UDCA may hav chmoprvniv ponial in IBD,

bu hir cacy sill nds o b valuad in randomizd sudis. Pains wih IBD

ar also a risk or dvloping LD whn hy ar on hiopurin ramn. Small bowl

adnocarcinoma may dvlop in pains wih CD locad in h small bowl, alhough

h absolu risk or his malignancy is low.



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MMH Classn1, FP Vlggaar1, KM tyga1, PD Sirsma1, HR van Buurn2

1Dparmn o Gasronrology and Hpaology, Univrsiy Mdical Cnr Urch,

2Dparmn o Gasronrology and Hpaology, erasmus MC - Univrsiy Mdical

Cnr Rordam

Journal o Hepatology, 2009 50: 158-64

CHaPter 3

High liim risk o cancr in primary sclrosing

cholangiis



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34 |CHAPteR 3

Absrac

Bckgound

Primary sclrosing cholangiis (PSC) pains ar a risk or dvloping

cholangiocarcinoma (CCA) and colorcal carcinoma (CRC).

aims & Mhods

Our aim was o assss h risk o malignancis and hir infunc on survival.

Daa rom PSC pains diagnosd bwn 1980 and 2006 in wo univrsiy

hospials wr rrivd. th Kaplan-Mir mhod and a im-dpndn Cox

rgrssion modl wr usd o calcula risks o malignancis and hir infunc

on survival.

rsuls

211 Pains wr includd, 143 (68%) wr mal and 126 (60%) had infammaory

bowl disas (IBD). Mdian ransplanaion-r survival was 14 yars. th risk o

CCA ar 10 and 20 yars was 9% and 9%, rspcivly. In pains wih concomian

IBD h 10-yar and 20-yar risks or CRC wr 14% and 31%, which was

signicanly highr han or pains wihou IBD (2% and 2% (p= 0.008)). CCA,

cholangiis, and ag a nry wr indpndn risk acors or h combind ndpoin

dah or livr ransplanaion. Risk acors or h ndpoin dah wr CCA, CRC,

ag, and sympomaic prsnaion.

Conclusions

Pains wih PSC and IBD hav a high long-rm risk o dvloping CRC and his

risk is abou hrold highr han h risk or CCA. Boh malignancis ar associad

wih dcrasd survival.



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35Malignancis in PSC |

Inroducion

Primary sclrosing cholangiis (PSC) is a chronic disas, characrizd by infammaion

and brosis o h inra- and xrahpaic bil ducs 1,2. th iology is unknown and

a hrapy o sop or rvrs progrssion o h disas is no availabl. Apar rom

h dvlopmn o dcompnsad livr cirrhosis wih ransplanaion as h only

civ ramn, h li xpcancy o PSC pains is sriously hrand by h

unprdicabl occurrnc o cholangiocarcinoma (CCA) and colorcal cancr (CRC).

th rpord ovrall risk or CCA varis rom 8% o 36% 3-6 and h 10-yar cumulaiv

incidnc rom 11% o 31% 3,7-9. ths highly variabl rsuls ar probably largly

xplaind by dirncs in pain slcion and duraion o ollow-up. Fw sudis

hav assssd h risk o CRC in PSC. Up o 90% o pains wih PSC hav

concurrn infammaory bowl disas (IBD), a major risk acor or CRC 10,11. I is

sill dbad whhr PSC carris an addiional and indpndn risk or CRC. th

rqun us o colorcal noplasia (dysplasia and CRC) insad o CRC as clinical

ndpoin o sudis conribus o h diculy o apprcia h acual CRC risk.

Broom al. 12 ound cumulaiv risks or colorcal noplasia o 9%, 31%, and

50% ar an IBD disas duraion o 10, 20, and 25 yars, rspcivly. In conras,

ohrs rpord no signican dirnc in CRC risk bwn pains wih PSC-IBD

or IBD alon 13-15. th aim o his sudy was o assss h risk o malignancis, in

paricular CRC and CCA, as wll as hir impac on survival in a larg and long-rm

ollow-up sudy o Duch PSC pains.

Mhods

Pins

All pains diagnosd wih PSC in h priod January 1980 - May 2006 wr

idnid rom wo daabass (endobas III, Olympus and h cnral hospial pain

rgisraion sysm) a h Univrsiy Mdical Cnr o Urch (UMCU) and h

erasmus MC Univrsiy cnr, h lar bing on o h hr livr ransplancnrs in h Nhrlands. PSC pains, sn a h UMCU, wih an indicaion or

livr ransplanaion wr rrrd o Rordam.

th diagnosis o PSC was basd on ypical ndings on cholangiography 16, or h

prsnc o characrisic hisological livr abnormaliis (pri-cholangiolar onion-

skin brosis, 17 in combinaion wih an lvad srum alkalin phosphaas and h

prsnc o IBD. th ons o PSC was dsignad as h da o h rs

abnormaliis on cholangiography or livr hisology. Pains wih bil duc

abnormaliis aribuabl o ohr causs such as bil duc surgry, ischmia, poral

vin hrombosis, or auoimmun pancraico-cholangiis wr xcludd 18-20.



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36 |CHAPteR 3

Collcion o d

Daa wr rrivd rom h mdical rcords and compurizd hospial daabanks.

Missing inormaion was compld by conacing h pains physician. Daa

collcd a h im o PSC diagnosis includd: im o ons o sympoms,

prsnc, xnsion, duraion and yp o IBD, asympomaic or sympomaic

(dnd as: prurius, jaundic, aigu, cholangiis, ascis, varical blding, hpaic

ncphalopahy or CCA) prsnaion, mdical hisory, and laboraory daa. th

diagnosis o IBD was basd on ndoscopic and hisological ndings.

During ollow-up, h ollowing daa and vns wr collcd: da and caus o

dah, livr ransplanaion, bacrial cholangiis, dominan bil duc sricurs,

diagnosis and hrapy o malignancis, nwly dvlopd IBD wih xn and duraion

o h disas, and paricipaion in a CRC survillanc program. Hisological criria

by Riddll al. or diagnosing coliis-associad-dysplasia and carcinoma wr

applid 21. Dysplasia was no considrd par o h diagnosis CRC. For his sudy

survillanc was dnd as colonic survillanc according o h AGA guidlins 22.

thror, pains who had (incidnal) ollow-up colonoscopis, bu no according

o a xd im schdul and wihou mulipl biopsis, wr no considrd as

having paricipad in a survillanc program. A dominan bil duc sricur was

dnd as a sricur wihou malignan caus ha rquird inrvnion which

would lad o a 50% dcras o bilirubin wihin wo monhs. end o ollow up was

ihr h nd o h sudy (May 2006), dah, or im o las visi in cas pains

wr los-o-ollow-up.

Sisicl anlysis

Follow-up commncd a h im ha a diagnosis o PSC was mad. Primary

ndpoins o h sudy wr CRC, CCA, and livr ransplanaion. Survival and risk

analyss wr prormd using h Kaplan-Mir mhod 23. Groups wr compard

using h log-rank s. Wih rspc o CCA, wo spara analyss wr mad;

on wih and on wihou bil duc umours diagnosd wihin six monhs ar PSC

was dcd. For h cumulaiv risk o CRC, cnsoring was prormd or

colcomy.th prognosic signicanc o nry daa was drmind by univaria analysis (log

rank and Cox rgrssion). A im-dpndn Cox rgrssion modl was usd or

mulivaria analysis o boh nry and ollow-up variabls indpndnly rlad o

h ndpoins dah or livr ransplanaion. In a spara analysis, h infunc o

malignancis on dah alon was drmind, also including pains ar livr

ransplanaion. A mulivaria analysis wih nry variabls was prormd o assss

ponial risk acors or CCA and CRC. All saisical analyss wr don wih SPSS

12.0. P-valus


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Rsuls

Pin chcisics dignosis o PSC

two hundrd lvn pains (143 mals) wr includd (tabl 1). th mdian ag

a diagnosis was 33 yars (rang 11-72) or mals and 40 yars (rang 11-75) or

mals. Svny-six (36%) pains wr sympomaic a h im o diagnosis.

th mos prvaln sympom was jaundic (n=43). In mos cass (84%) diagnosis

o PSC was basd on cholangiographic ndings. Hisology was availabl in 148 (70%)

pains and showd cirrhosis in 23 cass. Concurrn IBD was prsn in 126 (60%)

pains o which 23 (18%) had Crohns disas, all wih colonic involvmn. to

rul ou h diagnosis o IBD in asympomaic pains (n=85), colonoscopy was

prormd in 62% o hs pains. th mdian inrval bwn h iniial diagnosis

IBD and subsqun PSC was 6.9 yars (rang 0-37.7).

tbl 1. enry characrisics o 211 pains wih primary sclrosing cholangiis

Vibl n=211

Sx, mal (%) 143 (68)

Ag a diagnosis PSC * (yrs) (mdian (rang)) 35 (11-75)

Prsnaion, sympomaic (%) 76 (36)

Hisology, cirrhosis 1 (%) 23 (11)

IBD * (%) 126 (60)

- No 2 85 (40)

- Ulcraiv coliis 93 (44)

- Crohns disas 23 (11)

- Indrmina coliis 10 (5)

Inrval IBD-PSC (yrs) (mdian (rang)) 6.9 (0-38)

Prvious colcomy 11 (5)

Bilirubin (mol/L)3 (normal 3-21) 17 (4-400)

Alkalin phosphaas (U/L) (normal


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38 |CHAPteR 3

Follow up

th mdian ollow-up was 9.0 yars (rang 0.3-25 yars); 15% (n=32) o h pains

wr los o ollow-up. Fory-v (21%) pains did during ollow up and 49 (23%)

pains undrwn livr ransplanaion. th simad mdian ransplanaion-r

survival o h nir cohor was 14 yars. Pains wih a sympomaic prsnaion

had a signicanly lowr ransplanaion-r survival ra han hos wih an

asympomaic prsnaion (p=0.001) (Figur 1). IBD was nwly diagnosd in 33/85

(39%) pains wihou concurrn IBD a nry. Consqunly, h oal prvalnc

o IBD in his cohor was 75%.

th 10-yar and 20-yar risks or dvloping bacrial cholangiis wr 42% and

57%, rspcivly. th risk o a dominan srucur was 35% and 39% ar disas

duraion o 10 and 20 yars, rspcivly.

Mlignncis

Malignancis wr h mos rqun (44%) caus o dah (n=45) in our cohor.

CCA and CRC wr h caus o dah in 11 and 5 pains, rspcivly. th scond

lading caus was livr ailur (tabl 2).

During ollow up, 39 (19%) malignancis wr diagnosd (tabl 3). Sixn (41%)

pains dvlopd CRC and 15 (39%) CCA. Ohr malignancis includd gallbladdr

cancr (n=2), pancraic cancr (n=1), lymphoma (n=3), mlanoma (n=1), and gasric

cancr (n=1).

All 16 CRC pains had concurrn IBD, alhough in on cas IBD was diagnosd

Figu 1b. Kaplan-Mir plo o h ransplanaion-r survival (+ 95% Condnc inrval) or 211

pains wih primary sclrosing cholangiis wih (Figur 1a) or wihou (Figur 1b) a sympomaic

prsnaion. A saisically signican dirnc was ound bwn boh groups (p=0.001, Log rank

s)



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six monhs ar PSC had bn diagnosd. Mdian inrval bwn h diagnoss

PSC and CRC was 8.3 yars (rang 0-18.2) and h IBD-CRC inrval was 12.6 yars

(rang 0-34.5). In pains wih concurrn IBD h 10-yar and 20-yar risks or CRC

wr 14% and 31%, rspcivly, which was signicanly highr han in pains

wihou IBD (2.3% (p= 0.008)) (Figur 2). th simad risk o CRC in h nir

cohor o pains ar 10 and 20 yars was 9% and 22%, rspcivly. th majoriy

o CRCs (63%) was locad in h cacum and h ascnding and ransvrs colon.

tbl 2. Causs o dah in 45 pains wih primary sclrosing cholangiis

n=45 (%)

Livr ailur 13 29

Cholangiocarcinoma 11 24

Colorcal carcinoma 5 11

Ohr malignancis 4 9

During/ wihin 30 days ar livr ransplanaion 4 9

Spsis ar colcomy 4 9

Cardiac arrs 2 4

Pulmonary mbolism 1 2

Unknown 1 2

Figu 2. Kaplan-Mir plo o h cumulaiv risk (+ 95% Condnc inrval) o cholangiocarcinoma

or 211 pains wih primary sclrosing cholangiis



40/132

40 |CHAPteR 3

Hal o h pains who dvlopd CRC did no paricipa in an ndoscopic CRC

survillanc program. Ninn (9%) pains dvlopd dysplasia, o which 12

undrwn colcomy (63%). two o h 19 pains wih low grad dysplasia

undrwn rgular survillanc colonoscopy, whras in 5 o h 19 pains dysplasia

was ound ar colcomy had akn plac or xacrbaion o h coliis. th 10-

yar and 20-yar risk or dysplasia was 15% and 30% or pains wih IBD, and

2.3% and 21% or pains wihou IBD a h im o diagnosis PSC, rspcivly

(p=0.02).

Figu 3. Kaplan-Mir plo o h cumulaiv risk (+ 95% Condnc inrval) o colorcal cancr or

211 pains wih primary sclrosing cholangiis wih (- - -) or wihou () concurrn IBD. A saisically

signican dirnc was ound bwn boh groups (p= 0.008, Log rank s)

tbl 3. Malignancis in 39 pains wih primary sclrosing cholangiis

n=39 (%)

Colorcal carcinoma 16 41

Cholangiocarcinoma 15 39

Non Hodgkin lymphoma 3 8

Gall bladdr cancr 2 5

Pancraic cancr 1 3

Gasric cancr 1 3

Mlanoma 1 3



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Fin pains dvlopd CCA. Mdian inrval bwn h diagnosis PSC and

CCA was 2.5 yars (rang 0-9.8 yrs). th simad risk o CCA ar 10 and 20

yars was 9%. Ar xcluding umours diagnosd wihin six monhs o nry (n=4),

h cumulaiv risk dcrasd o 7% (Figur 3). No signican dirncs in risk

wr ound or pains wih and wihou concurrn IBD (p= 0.386).

th occurrnc o CRC was signicanly associad wih h ndpoin dah

(tabl 4). Ohr indpndn risk acors or his ndpoin wr occurrnc o CCA,

ag a nry, and sympoms a prsnaion. Mulivaria analysis including im-

tbl 4. Uni- and mulivaria analysis including im-dpndn variabls or ndpoin dah, dah or

livr ransplanaion, CRC, or CCA, rspcivly, in 211 pains wih primary sclrosing cholangiis

endpoin Dh

Univaria Analysis Mulivaria Analysis

Variabl HR 95% CI p-valu HR 95% CI p-valu

Colorcal carcinoma 4.9 2.2-10.8 0.000 8.5 3.2-22.7 0.000

Cholangiocarcinoma 198.2 77.3-508.5 0.000 171.8 57.1-517.4 0.000

Ag 1.1 1.0-1.1 0.000 1.1 1.0-1.1 0.000

Sympomaic prsnaion 2.2 1.2-4.0 0.008 2.4 1.2-5 0.016

Bacrial cholangiis 3.0 1.6-5.6 0.000 no in modl

Comorbidiy 4.6 1.6-13.3 0.004 no in modl

endpoin Dh o Liv nsplnion


Cholangiocarcinoma 99.9 45.0-221.9 0.000 43.2 18.0-103.8 0.000

Bacrial cholangiis 5.8 3.7-9.1 0.000 3.9 2.4-6.4 0.000

Ag 1.0 1.0-1.1 0.000 1.0 1.0-1.0 0.018

Sympomaic prsnaion 2.0 1.3-3.1 0.001 no in modl

Cholcyscomy 2.3 1.4-3.8 0.002 no in modl

exnsion IBD 0.5 0.3-0.8 0.010 no in modl

endpoin CrC


Concurrnc o IBD 8.6 1.1-64.8 0.038 no in modl

exnsion o IBD 3.4 1.3-9.0 0.017 no in modl

endpoin CCa


Ag 1.0 1.0-1.1 0.021 no in modl

HR: Hazard Raio; 95% CI: 95% Condnc Inrval



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42 |CHAPteR 3

dpndn variabls or h combind ndpoin dah or livr ransplanaion showd

ha ag a nry, CCA, and bacrial cholangiis wr indpndn risk acors.

Cholcyscomy, srum bilirubin, hmoglobin lvl and sympoms o livr ailur

(ascis, ncphalopahy, sponanous bacrial prioniis, hpaornal syndrom)

wr also saisically signican in univaria analysis, bu wr xcludd rom h

mulivaria modl bcaus o h alrady known associaion bwn livr ailur

and livr ransplanaion. A similar analysis or h singl ndpoin CRC showd ha

concurrnc and xn o IBD wr o signican valu (tabl 4). For h ndpoin

CCA, only ag a prsnaion was a signican risk acor.

Discussion

this larg and long-rm cohor sudy showd ha PSC-IBD pains hav a high li-

im risk or CRC and ha his risk is subsanially highr han ha or CCA. Furhrmor,

occurrnc o CRC in hs pains lads o rducd survival chancs.

Fw and conficing daa on CRC risk in PSC hav bn rpord. Lous al. 14

ound an acuarial incidnc a 10 yars o only 4%, whras Kornld al. 24

rpord a 10-yar risk o 25%. th lar nding, howvr, was basd on only v

CRC cass. Comparison o our rsuls wih hos o Broom al. 12 is hamprd

by h ac ha colorcal noplasia, including dysplasia and CRC, was akn as

sudy ndpoin. I w would assum ha colorcal dysplasia is h immdiaprcursor lsion o all IBD-associad CRCs, our sudy as wll as h on by Broom

al. ound a 20-yar risk o dvloping CRC in PSC o approximaly 31%. this

prcnag may b an undrsimaion as som o our pains undrwn

prococolcomy whn dysplasia was ound during survillanc colonoscopy. Our

high 20-yar risk o CRC (31%) was signicanly highr han h risk o 8% rpord

in a ma-analysis on CRC risk in IBD wihou PSC publishd in 2001 10. thror,

our obsrvaion provids urhr vidnc ha PSC promos colorcal

carcinognsis in IBD 25-28. No nw risk acors or CRC addiional o h ons ha

ar alrady known wr ound in h currn sudy. Only concurrnc and xn oIBD wr ound o b risk acors or dvloping CRC. thr pains who did no

hav concurrn IBD a diagnosis PSC dvlopd IBD and colorcal dysplasia,

rsuling in a 20-yar dysplasia risk o 21% in pains wihou IBD a diagnosis PSC.

th mdian inrval bwn h diagnosis PSC and IBD in hs hr cass was

5.3 yars (rang 0.5-14.3 yars).

th 10-yar and 20-yar acuarial incidncs o CCA (9% and 9%) wr signicanly

lowr han hos or CRC. Furhrmor, his risk o 9% ar 10 yars was lowr

han has bn publishd prviously 7. Ar xcluding CCAs ha wr diagnosd

wihin a six-monh priod ar dcion o PSC, h 10-yar and 20-yar risks wr



43/132


7% and 7%, rspcivly. this is probably jusid by our obsrvaions which mak

i likly ha, in rrospc, hs arly CCAs probably wr prsn a h im o

h iniial diagnosic valuaions, alhough w acknowldg

ha a priod o six monhs is arbirary. I was rmarkabl ha dspi h narly

qual absolu numbrs o CRCs (n=16) and CCAs (n=15), h long-rm risk was

qui dirn. this is xplaind by h ac ha narly all CCAs prsnd wihin

h rs hr yars ar PSC had bn diagnosd. th majoriy o pains wr

no y cnsord, hus sill in ollow-up a ha im, which rducd h impac o a

singl CCA on h acuarial incidnc. In conras, h incidnc o CRC was no

limid o h rs hr yars o ollow-up. Our rlaivly low risk o CCA may b

an undrsimaion, bcaus auopsy was no prormd in all cass dying rom

ohr causs. Bsids ag a prsnaion o PSC, no ohr indpndn risk acors

or CCA wr ound. earlir sudis rpord an associaion bwn IBD and

CCA 29,30. this may b du o h ac ha h diagnosis PSC could no b dcd

accuraly a a im whn rliabl non-invasiv cholangiography was no availabl.

Ohr, mor rcn sudis did no nd an associaion bwn IBD and CCA 31,32.

this is h rs sudy ha dmonsras ha occurrnc o CRC in PSC pains

rducs pain survival. Boh h high risk o CRC and is impac on survival

undrlin h suggsd bncial c o colonic survillanc in PSC-IBD

pains. Only hal o h pains undrwn survillanc colonoscopy according

o a sric proocol. During h 1980s, h currn accpd guidlins wr no

y implmnd which xplains his rlaivly low numbr 22. this sudy did nohav h corrc dsign o valua h c o survillanc on survival. In h

mulivaria analysis wih h combind nd-poin livr ransplanaion and dah

(ransplanaion-r survival), CRC was no a saisically signican im-

dpndn variabl (tabl 4). An xplanaion or his may b ha malignancy was a

conraindicaion or livr ransplanaion wihin a priod o v yars ar diagnosis.

CCA rmaind signican in his analysis, du o h wll-known narly 100% aal

oucom o his malignancy 7,33,34.

A high 10-yar and 20-yar risk, 42% and 57%, rspcivly, was obsrvd or

bacrial cholangiis. Mos pains wr diagnosd wih PSC a a im ha invasivndoscopic rrograd cholangiography, and no MRCP, was h main diagnosic

mhod. Howvr, considring h im inrvals bwn diagnosis and h

occurrnc o bacrial cholangiis his sms no a saisacory xplanaion or h

incidnc o his complicaion ound in his sudy. Bacrial cholangiis was associad

wih h dvlopmn o dominan bil duc snoss in h majoriy o h pains

(62%). this may b anohr xplanaion or h high risk o dvloping bacrial

cholangiis.

thr ar svral limiaions o his sudy including h lack o a conrol group.

I is dicul o nd a rliabl conrol group ha machs h sudy group bcaus



44/132

44 |CHAPteR 3

i is known ha h cours o IBD dirs in pains wih PSC rom hos wihou

PSC 35,36. IBD in PSC pains is characrizd by a high prvalnc o pancoliis wih

rcal sparing, a mild and somims asympomaic cours and a lowr colcomy

ra. Scondly, h calculaion o h cumulaiv risk o colorcal noplasia, CRC

and CCA is basd on 30, 16 and 15 pains rspcivly. Nonhlss, as poind

ou prviously, his is sill a ar highr numbr han in ohr sudis 12,24,36. Finally, all

pains wr rad in a riary rrral hospial, which may hav rsuld in bias

du o inclusion o pains wih cancr risks diring rom hos in h gnral PSC

populaion.

In conclusion, PSC-IBD pains hav a high risk o dvloping CRC ovr im and

his has a ngaiv impac on survival o hs pains. thror, i sms likly

ha his pain cagory in paricular may bn rom colorcal survillanc

ndoscopy.

Acknowldgmns

W hank R. Sllao, saisician, or hr assisanc wih h analyss.



45/132


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