EQUIP Training session 2 Introduction to dye and optical staining and classification methods

Session 1 overview EQUIP goals review

Session 2 goals Paris classification system review Dye and optical staining methods Role in detection Role in classification; Kudo & Sano Understand settings they are use Utilize to differentiate neoplastic potential By the end of this session, participants will be understand the three major classification systems (Paris, Kudo, Sano), understand the settings in which they are used, understand the utility each has in detection and classification and show proficiency in their application

The Paris Classification Snare polypectomy EMR en bloc Or piecemeal EMR en bloc, ESD, or surgery Adenoma High grade adenoma Carcinoma Histology Resection I-p I-s II-a -b -c Paris class if probably the most recognized and used. It refers to the morphology of a lesion. III mixed

Paris Classification I-p (pedunculated) I-s (sessile) II-a (flat elevated) II-b (flat flat) IIc (flat depressed) III (flat ulcerated)

Dye and optical “staining” Chromoendoscopy Detection Classification: Kudo pit patterns Narrow band imaging Sano capillary pattern Classification methods test cases

Chromoendoscopy Detection Classification Does pan-chromoendsocopy increase adenoma detection? Classification Kudo pit patterns

Pan Chromo in Average Risk Persons A Randomized Controlled Trial Lapalus, Endoscopy, 2006;38:444

Chromo in Average Risk N = 292 Chromo (146) Standard (146) Pts with Adenomas 40% 36% (p=0.47) Total adenomas 115 87 (p= 0.18) Total Hyperplastic 110 67 9 (p=0.03) Colonoscopy time 27 min [14-75] 18 [8-60] (p<0.001)

Meta-analysis of Pan Chromo in Average Risk Patients 4 Randomized Controlled Trials Odds Ratio 95% CI Patients with any adenoma 1.61 1.24-2.09 3 or more adenomas 2.55 1.49-4.36 Brown; Cochrane DB Syst Rev, 2007;4:6439

Does Routine “Pan Chromoendoscopy” Increase Adenoma Detection? Yes, but with longer procedure times

Kudo pit patterns Objectives Understand What Kudo pit patterns represent Use of dye staining to observe pit patterns Use Kudo pit patterns to: Distinguish neoplasia from non-neoplasia Differentiate neoplastic lesions in terms of degree of dysplasia

Kudo pit patterns Developed for use in chromoendoscopy Indigo carmine remains in depressions (pits) The violet dyes actually stain the mucosa Results not replicated with NBI in absence of dye staining.

Kudo pit patterns Technique Feces & mucous must be washed away before staining 2 – 7ml applied to lesion, excess suctioned before observation Spray catheter or syringe injection for indigo carmine Violet dyes require 30 – 60 seconds to stain prior to observation

Kudo Pits = openings of the colonic crypts Pit pattern = arrangement of openings on mucosal surface Pit patterns categories Normal mucosa – pit pattern I Hyperplastic – pit pattern II Adenomatous – pit pattern III-L High grade adenoma: pit pattern III-s, and IV Cancerous – pit pattern V

Kudo non-neoplastic patterns I & II Type I: Normal mucosa Roundish pits with regular distribution Represent straight, non-branching crypts Type II: Hyperplastic Large star-like or “onion”-like pits, regular Explain

Kudo neoplastic patterns III-L : Adenomatous lesions III-L: Adenoma (low-grade) Tubular or round eLongated pits Pits are Larger than normal Explain

Kudo pit patterns Non-neoplastic Neoplastic Type II: Hyperplastic Type III-L: Adenoma Non-neoplastic lesions can be distinquished from neoplastic lesions based on the shape, size and regularity of the crypt. Compare the Kudo II Hyperplastic lesion shown on the left with the Type III-L adenoma on the right. Notice that the crypts become elongated and larger in the adenoma compared to the hyperlastic lesion. Tubular or round, elongated, large pits. Large, star like (or onion) crypts. Regular pattern

Kudo neoplastic patterns III-s, IV: High grade lesions Compactly arranged tubular (or round) pits Pits are Smaller than normal Tend to be depressed lesions IV: Pits look branched or gyrus like Often have a focal cancer Explain

Kudo pit patterns Non-neoplastic Neoplastic Type II: Hyperplastic Type III-s: High grade lesion Non-neoplastic lesions can be distinquished from neoplastic lesions based on the shape, size and regularity of the crypt. Compare the Kudo II Hyperplastic lesion shown on the left with the Type III-L adenoma on the right. Notice that the crypts become elongated and larger in the adenoma compared to the hyperlastic lesion. Compact, smaller than normal pits. Large, star like (or onion) crypts. Regular pattern

Kudo pit patterns Adenoma Advanced adenoma Type III-L: Type V: High grade lesion Neoplastic lesions can be further distinguished as adenomatous vs. cancerous based on the organization of the MC structure. Here the question doesn’t become whether the Meshed capillaries are present but rather the organization of the capillary pattern around the glands Pits look branched or gyrus like Tubular, elongated, large pits.

Kudo pit patterns Adenoma Advanced adenoma Type III-L: Type III-s: High grade lesion Neoplastic lesions can be further distinguished as adenomatous vs. cancerous based on the organization of the MC structure. Here the question doesn’t become whether the Meshed capillaries are present but rather the organization of the capillary pattern around the glands Pits look branched or gyrus like Tubular, elongated, large pits.

Kudo neoplastic patterns V: Carcinomas V: Cancer Irregular pit pattern; Vi Advanced cancers (Vn) may be rough & ulcerated May be devoid of pits or “non-structural” pattern

Kudo Pit Patterns IIIs IV V I II IIIL

The Kudo Classification Pit Patterns Histology Management Hyperplastic Nothing II Snare polypectomy III-L Adenoma III-S High grade adenoma EMR en bloc Or piecemeal IV EMR en bloc, ESD, or surgery V Carcinoma

Kudo Sensitivity/specificity for prediction

Narrow band imaging Detection Classification How can NBI be used in detection? Does NBI increase adenoma detection? Classification Sano capillary patterns overview

Does NBI Increase Adenoma Detection Probably (compared to standard def. white light, but not HD white light) Does not increase procedure time

Does NBI Increase Adenoma Detection White Light NBI Hyperplasia Adenoma Advanced Ad

Does NBI Increase Adenoma Detection Systematic Review: Randomized Trials Study Pts with adenoma NBI Pts with adenoma WLE adenoma/pt NBI WLE O.R. NBI vs WLE Rex 2007 N=217 65% 67% 1.86 1.82 0.90 (0.61-1.34) Adler 2007 N= 198 23% 17% 0.33 0.26 1.27 (0.88-1.84) Inoue 2008 N=122 42% 34% 0.84 0.55 1.55 (1.14-2.11) Pooled 44% 41% 1.06 0.96 1.23 (0.93-1.61) Van den Broek et al. GIE 2009;69:124

Does NBI Increase Adenoma Detection Back to Back Trials Adenoma/pt NBI WLE Rastogi 2008 N=40 0.73 1.08 East 2007 N=62 0.34 0.40 Gross [in press] N=91 0.25 0.34*

Mayo Clinic, Jacksonville, FL, USA A PROSPECTIVE RANDOMIZED BACK-TO-BACK TRIAL COMPARING NARROW BAND IMAGING TO CONVENTIONAL COLONOSCOPY FOR ADENOMA DETECTION Gross SA, Buchner AM, Cangemi JR, Wolfsen HC, DeVault KR, Crook J, Picco MF, Loeb DS, Woodward TA, Raimondo M, Wallace MB Mayo Clinic, Jacksonville, FL, USA

Tandem Double Blind Trial NBI vs White Light Tandem Double Blind Trial Adenomas per patient Standard (Std) 11/19 58% NBI 8/19 42% Standard first (n=44) ‘Miss rate’: Standard: 42% NBI: 16% p = 0.003 NBI 16/19 84% Std 3/19 16% NBI first (n=47) Gross, Wallace et al. Gastro/DDW 2008 No. of patients with > 1 adenoma

Sano capillary patterns Developed with Narrow band imaging Narrow spectrum allows visualization of capillary pattern in superficial layer Capillary vessels appear brown on NBI Capillary pattern around glands change with neoplasia 3 capillary pattern types CP I: Normal mucosa or hyperplastic lesion CP II: Adenomatous lesion CP III: Cancer (further subdivided into A & B)

Sano capillary patterns CP I CP I: Normal mucosa and hyperplastic polyps Hyperplastic lesions appear light brown on NBI Messed capillaries not seen or faint, If MC seen (large lesions) will be in a regular honeycomb pattern The first distinction; hyperplastic vs adenoma

Sano capillary patterns CP II CP II: Adenomatous lesions Adenomas appear dark brown on NBI MC clearly seen Round, oval or honeycomb pattern Pattern may be elongated with larger diameter

Sano capillary patterns CP III CP III: Cancerous lesions MC clearly seen Increased density of microvessels Unevenly sized thick capillaries Branching and irregularity Further subdivided based on depth of invasion CPIII A: Sub-mucosal invasion <1000 CPIII B: Sub-mucosal invasion > 1000

Sano capillary patterns CP I: Normal mucosa Hyperplastic lesions CP II: Adenomatous lesions First we’ll look at hyperplastic vs. adenomatous lesions. When using Sano to make this distinction, the first question is whether you can see the capillary patterns. If they are not visible or only faintly visible then it’s either normal mucosa or a hyperplastic lesion. If the meshed vessels are clearly visible then what is the pattern? With current resolution, a honeycomb pattern may be faintly seen in large hyperplastic lesions. However the meshed capillaries in adenomas are very clearly seen and are elongated and large in comparison. Meshed capillary vessels （‐） Meshed capillary vessels （+）

Sano capillary patterns Differential diagnosis of small lesions 92 eligible patients; 150 lesions <10mm 39 (26%) hyperplastic 111 (74%) adenoma Invasive cancers excluded Magnifying NBI (no dye) Endoscopic diagnosis (neoplastic vs. non- ) Based on presence or absence of MC Accuracy compared to pathologic diagnosis

Sano capillary patterns Differential diagnosis of small lesions (I vs Sano capillary patterns Differential diagnosis of small lesions (I vs. II) MC vessels by NBI and histologic examination Neoplastic Non-neoplastic MC vessels (+) 107 3 MC vessels (-) 4 36 Simple distinction between presence or absence of meshed capillaries by NBI had high diagnostic accuracy, negative and positive predictive values, sensitivity and specificity. Sensitivity: 96.4%, Specificity: 92.3%, Accuracy: 95.3%, NPV (negative predictive value): 90.0%, PPV (positive predictive value): 97.3% MC, meshed capillaries

Sano capillary patterns CP II: Adenomatous lesions CP III: Cancerous lesions Neoplastic lesions can be further distinguished as adenomatous vs. cancerous based on the organization of the MC structure. Here the question doesn’t become whether the Meshed capillaries are present but rather the organization of the capillary pattern around the glands No honeycomb pattern. Irregularity of size, complex branching, disruption, or irregular winding. Round, oval, honeycomb like pattern. May be elongated and large diameter.

Sano capillary patterns Prediction of early colorectal neoplasia 104 patients with 139 lesions Only CP II or CP III lesions included

Sano capillary patterns Prediction of neoplasia (II vs. III) Histological diagnosis LGD HGD/ invasive CA CP II (n =103) 100 3 CP III (n = 31) 28 Sensitivity: 90.3%, Specificity: 97.1%, Accuracy: 95.5%, NPV (negative predictive value): 97.1%, PPV (positive predictive value): 90.3% LGD, low grade dysplasia; HGD, high grade dysplasia

Sano capillary patterns CP III types: depth of invasion CPIII-A: Cancerous lesion; (pSM & pSM1) MC clearly seen, CPIII-B: Cancerous lesion; (pSM2-3) Sano capillary pattern type III are the cancerous lesions. They have been further subdivided into two subtypes based on depth of invasion.

Sano capillary patterns CP III A: Cancerous lesions CP III B: Cancerous lesions Neoplastic lesions can be further distinguished as adenomatous vs. cancerous based on the organization of the MC structure. Here the question doesn’t become whether the Meshed capillaries are present but rather the organization of the capillary pattern around the glands Meshed capillary vessels characterized by: blind ending, branching and curtailed irregularly Lack of uniformity High density of capillary vessels Nearly avascular or loose micro capillary vessels

Sano capillary patterns Diagnostic accuracy of depth of invasion 127 patients; 130 lesions CP type IIIA/IIIB Endoscopic (IIIA) or surgical resection (IIIB)

Sensitivity, specificity and diagnostic accuracy of CP Type III Histological diagnosis M*, SM-superficial (SM1)** SM-deep (SM 2-3)# CP type IIIA 86 5 CP type IIIB 11 28 Sensitivity: 84.8%, Specificity: 88.7%, Accuracy: 87.7%, NPV (negative predictive value): 94.5%, PPV (positive predictive value): 71.8% *intramucosal cancer, ** SM superficial invasion (<1000 μm), # SM deep invasion (≥ 1000 μm) Ikematsu et al, BMC Gastroenterology 2010, 10:33

I II IIIA IIIB Capillary pattern Schema Endoscopic findings Meshed capillary vessels （‐） vessels （+） Capillary vessel surrounds mucosal glands Meshed capillary vessels characterized by: blind ending, branching and curtailed irregularly Lack of uniformity High density of capillary vessels Nearly avascular or loose micro capillary vessels Schema Capillary pattern characteristics In summary, when analyzing a lesion using Sano there are three questions. Are the meshed capillaries visible? If visible what is the pattern? Is the structure organized or disorganized.

Test cases. Describe the following polyps in terms of: Paris shape Kudo (chromo) or Sano (NBI)