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Di fronte alla displasia intestinaleColon e Retto
G C SturnioloUniversità degli Studi di Padova
Dipartimento di Scienze Chirurgiche e Gastroenterologiche
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DIAGNOSIS OF DYSPLASIA Macroscopic heterogeneity
Flat
Itzkowitz et al., 2004
Elevated (polyp-like, DALM, ALM)
Gastroenterologia Padova, 2005
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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
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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
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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
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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
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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
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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
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Low Grade Tubuloglandular Adenocarcinoma (LGTGA): from LGD to Cancer
Harpaz , Am J Surg Pathol, 2006
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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
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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
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Autofluorescence improves neoplasia detection
NBI has a moderate accuracy for prediction of histology
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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
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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)
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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
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Gupta, Gatroenterology 2007
For any unit increase in inflammation score
a 3-fold increase of advanced neoplasia
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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
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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
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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
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• 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
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•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%