Di fronte alla displasia intestinaleColon e Retto

G C SturnioloUniversità degli Studi di Padova

Dipartimento di Scienze Chirurgiche e Gastroenterologiche

DIAGNOSIS OF DYSPLASIA Macroscopic heterogeneity

Flat

Itzkowitz et al., 2004

Elevated (polyp-like, DALM, ALM)

Gastroenterologia Padova, 2005

SURVEILLANCE IN IBD• 8-10 years for Crohn’s disease colitis and extensive

ulcerative colitis 15-20 years left sided ulcerative colitis

• Two-four random biopsies every 10 cm, additional samples of suspicious areas no<33biopsies

(British and American guidelines recommendations 2003)

Colonoscopic surveillance is able to reduce CRC-related mortality

Case-control studies

Vleggaar,AP&T,2007

RISK OF CRC IN UC & CD

Cumulative Incidence for CRC Based on Extent of Disease and Age at

Diagnosis

Cum

ula

tive C

RC

(%

)

0

10

20

30

40

0 20 30 40 50Age at diagnosis

pancolitis

Proctitis or ileal CD

Oldenburg, UEGW, 2008

Life-timeCumulative risk

Population based studies

Referral center studies

UC 3.7 9

colonic CD 2.7 6.9

NOT ALL PATIENTS WITH IBD HAVE THE SAME CRC RISK!

Rubin, World J Gastroenterol,2008

Factors that increase CRC risk

Factors that decrease CRC risk

Long duration of colitis

Extensive colonic involvement

Family history of CRC

PSC

Young age of IBD onset

Backwash ileitis

Severity of inflammation

Prophylactic total proctolectomy

Regular doctor visits

Colonoscopy

Chemoprevention

EARLY COLORECTAL CANCER IN IBD

Lutgens, Gut 2008

6.7% simoultaneously IBD/CRC 22% early CRC

*patient with left-sided colitis who developed CRC before 15 or 20 years

Microscopic classification

Low Grade Dysplasia High Grade Dysplasia

Itzkowitz et al., 2004; Lim et al 2003

DIAGNOSIS OF DYSPLASIA

Indefinite for Dysplasia

Interobserver agreement for LGD 0.06 – 0.39 between each pair of the 5 gastrointestinal pathologists

Low Grade Tubuloglandular Adenocarcinoma (LGTGA): from LGTGA to Cancer

Harpaz , Am J Surg Pathol, 2006

•LGTGA not a rare entity (11%)

•Relatively young patients (mean age 41.5 years) with extensive and long-standing colitis

•23% small size (max 2.2 cm) and flat, escape detection during initial gross examination

Low Grade Tubuloglandular Adenocarcinoma (LGTGA): from LGD to Cancer

Harpaz , Am J Surg Pathol, 2006

PROSPECTIVE TRIAL CHROMOENDOSCOPY vs RANDOM BIOPSIES

0

2

4

6

8

10

12

14

16

LGD HGD

Random Non-dye targed Dye targed

p=0.001p=0.057

79 UC 23 CD colitis

n°

of

pati

ents

Pts

Random NDT Dye-T Colectomy findings

1 Neg LGD No dysp No dysp

1 Neg LGD NR LGD LGDHGD

2 Neg Neg NR LGD LGD

MEDIAN TIMERandom/Non-dye targed: 22:11min Dye targed: 15:12 min

POST COLECTOMY FINDINGS

Marion, Am J Gastroenterol, 2008

NBI for the study of DYSPLASIA in UC: a pilot study

Matsumoto, Gastrointest Endosc, 2007

Honeycomb like Mild chronic inflammation

Tortuos pattern LGD

Tortuos pattern HGD

Colonoscopy Honeycomb Tortuous

Total

Protruding lesion

0%(0/18)

100%(2/2)

10%(2/20)

Flat mucosa 0.4%(1/228)

4.2%(2/48)

1.1%(3/276)

Total 0.4%(1/246)

8%(4/50)

1.6%(5/296)

NBI

+ p=0.003, * p=0.038,not confirmed with multiple testing

*

+

+ +

Incidence if dysplasia

Autofluorescence improves neoplasia detection

NBI has a moderate accuracy for prediction of histology

More detection of neoplasia 4.75-fold with 50% fewer biopsies

Kiesslich, Gastroenterology, 2007

Chromoscopy-guided endomicroscopy increases the diagnostic yield of intra-epithelial neoplasia in UC

Gastroenterologia Padova, 2008

Probability of finding CRC at colectomy for LGD/HDG

Dysplasia Probability of finding CRC

Reference

DALM 17/40 (43%) Bernestein, Lancet ‘94

HGD 10/24 (42%) Bernestein, Lancet ‘94

HGD 8/12 (67%) Connel, Gastrenterol’94

HGD 5/11 (46%) Rutter, Gastrenterol ’06

LGD 3/16 (19%) Bernestein, Lancet ‘94

LGD 2/10 (20%) Rutter, Gastrenterol ’06

LGD 2/11 (19%) Ullman, Gastrenterol ’03

LGD 3/8 (37%) Merlini ’06 (UEGW)

COLONOSCOPIC MARKERS FOR DYSPLASIA & CRC IN UC

Rutter Gut 2004

Multivariate analysis of Case Control Studies

Variable Group OR (95% CI) p Value

Normal colonic appearance No 1

Yes 0.38 (0.19, 0.73)

0.003

Post-inflammatory polyps* No 1

Yes 2.29 (1.28, 4.11)

0.005

Colonic stricture * No 1

Yes 4.62 (1.03, 20.8)

0.05

*Indicative of severe inflammation

Gupta, Gatroenterology 2007

For any unit increase in inflammation score

a 3-fold increase of advanced neoplasia

BLOCKING TNF-α IN MICE REDUCES CRC CARCINOGENESIS

TNF-alfa increases with time after AOM and DSS treatment proportionately to tumor formation

Popivanova, J Clin Invest, 2008

00,5

11,5

22,5

33,5

44,5

5

contro

l

Day 0

Day 7

Day 14

Day 28

Day 35

Day 56

TNF-alpha

m-R

NA

level

Anti TNF-α administration reduces number and tumor size

SECONDARY CANCER PREVENTION in LGD: COLECTOMY?

PALAZZO DELLA RAGIONE, PADOVA

•20% of concurrent CRC•No clinical feature discriminates progressors to no progressors• Progression to CRC even with surveillance•Once detected 9 X risk of CRC and 12 x risk of any advanced lesion (HGD, DALM, CRC) during surveillance•NNC(olonoscope) 6 for advanced histology and NNC 8 for CRC once LGD detected

•Incontinence•Adhesions•Pouchitis•Fertility

Dysplasia, CRC and IBD

• Understanding the definition, pathogenesis and biological significance of dysplasia is crucial to the proper management of CRC

• Chronic inflammation, the persistent state of tissue repair and cell renewal play a key role in colorectal carcinogenesis associated with IBD

• Colonoscopy plus biopsies is the main method for CRC prevention

• Chromoendoscopy and targeted biopsies have a greater yield for detection of dysplasia

• LGD is clinically important endpoint in the surveillance

• Endoscopic resectability determine the management of polypoid dysplasia in IBD

Dysplasia, CRC and IBD

•distance between the invasive tumor and the cauterized biopsy margin•tumor differentiation •status of lymphatic or vascular invasion (present or absent)

Prognostically significant histologic features

lymphnode +ve if LGD polpys:

•Colacchio 4%•Cranley 0%•Geraghty 0%•Kyzer 0% •Dell’Abate 0%

lymphnode +ve if HGD polpys:

•Cranley 18%•Geraghty 11.1%•Kyzer 5.6% •Dell’Abate 14.3%