From reflux to esophageal cancer. Josh Boys, MD TCV 2 nd year indentured servant

Transcription

1 From reflux to esophageal cancer Josh Boys, MD TCV 2 nd year indentured servant

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3 The Pathway Esophageal Squamous epithelium+reflux Columnar lined esophagus (CLE) or Cardiac mucosa Intestinal Metaplasia or Barrett s Esophagus (BE) BE+Dysplasia Esophageal Adenocarcinoma

4 The Players in the Game Esophagus Squamous epithelium Motility Cardia Cardiac mucosa (no parietal cells)? Oxyntocardiac mucosa (parietal cells) LES Fundus/Body/Antrum Chief cells (pepsinogen) Parietal cells (HCL and IF) G cells (Gastrin) Human Gastric Anatomy, MIT

5 Is the Cardiac mucosa normal or abnormal? Chandrasoma et al Autopsy study of the GEJ Pure cardiac mucosa was absent in 56% of patients All patients had oxyntocardiac mucosa (mucus and parietal cells) The measured maximum length of cardiac plus oxyntocardiac musoa was less than 0.5cm in 76% There was a tendency for the presence and extent of cardiac mucosa to increase with age Conclusion: cardiac mucosa is not a normal structure (controversial) Kilgore et al Autopsy study in a pediatric population 100% of cases had cardiac type mucosa w/ a mean length of 1.8mm

6 Reflux and the Danger Zone

7 Gastroesophageal Reflux Disease (GERD) Increased or abnormal exposure of the esophageal mucosa to refluxed gastric juice AKA

8 DeMeester and Ireland 1997 Dis Esoph Esophageal Epithelial Damage Distance by Exposure Correlation between acid exposure and length of cardiactype columnar epithelium

9 ph and Mucosal Injury Bremner et al Prevalence of mucosal injury Bremner et al. 1992

10 How bile makes it happen Side note: Normal volunteers taking 20mg omeprazole BID Spend 30% of 24hrs with A gastric ph < 4 Kuo and Castell 1996 Am J Gastro DeMeester 2000 ann surg

11 Kauer et al Bilirubin and Mucosal Injury

12 ph and the nature of refluxed material is critical in the distribution of intestinal metaplasia within a CLE Modulates stem cells? Alters expression of genes? i.e. Wnt, BMP-4, hedgehog and Cdx-2 Imamura et al. 2015

13 Among patients with Barrett s Bile exposure increases the risks of complications dysplasia Oberg et al J Gastrointest Surg

14 Patients who have the most mucosal injury have both gastroduodenal and acid reflux as opposed to pure gastric reflux

15 Barrett s Esophagus

16 What exactly is Barrett s esophagus? I know it when I see it

17 Where does Barrett s (intestinal metaplasia) come from?

18 How does Barrett s (intestinal metaplasia) happen? Squamous epithelial cell Circulating Bone Marrow stem cell Squamocolumnar Submucosal junction cell gland cell (Cardiac mucosa) Four Horsemen of the Apocalypse, an 1887 painting by Viktor Vasnetsov. Depicted from left to right are Death, Famine, War, and Conquest.

19 Circulating Bone Marrow Stem Cell

20 Esophageal Squamous epithelium to Barrett s It s complicated and not completely known It s likely at least a 2 step process Step 1: Trasndifferentiation of squamous to columnar cells Step 2: Development of Barrett s (intestinal metaplasia w/ goblet cells)

21 Step 2: Barrett s Esophagus Related to: Nature of refluxed gastric juice bile is important Correlated to the length of columnar lining Location of the IM is not random Campos et al. 2001

22 Location, Location Location Paull et al NEJM Systematic histology of 11 patients with columnar lined esophagus Biopsies obtained from the lower esophageal sphincter and then at interval of 1-3cm into the body of the esophagus IM was always proximal

23 Is all Barrett s equal? Fitzgerald et. al Gut 26 patients w/ BE > 3cm (IL-10) 20 non-dysplastic BE 6 HGD/carcinoma (4/6 w/ distal Ca) Assessed inflammatory markers along length of BE from cell culture IL-1 IL-8 IL-10 Inflammatory gradient w/ maximal inflammation at the new SCJ Distal BE segment is characterized by a relatively non-inflamed epithelium w/ assoc high levels of IL-10

24 Locaction, Location, Location cont The hallmark feature of intestinal metaplasia = Goblet cells The highest density is also at the proximal columnar segment Biopsies for Barrett s should be focused near the squamocolumnar junction Chandrasoma et al. 2001

25 Incidence of BE? Tough to know, but somewhere between 0.45% to 3.3% of all patients undergoing EGD 12% of patients undergoing EGD for GERD 3-6% with long segment BE Autopsy series (Cameron et al Gastroenterology) 7 cases out of 733 unselected autopsies 5/7 (70%) were first detected at autopsy Estimate 376 cases per 100,000 population For every known patient with Barrett s, there might be 20 or more unrecognized one in the general population

26 Screening for BE ACG and AGA Consider in men with > 5 years and/or frequent symptoms of GERD and two or more risk factors for BE or EAC. Age > 50 Caucasian Central obesity Current or past history of smoking Confirmed family history of BE or EAC

27 Screening/Surveillance of BE We screen and do surveillance of people at risk or who have Barrett s esophagus (intestinal metaplasia) because we want to catch dysplasia and esophageal adenocarcinoma early

28 Why is finding esophageal cancer early important?

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30 RR 0.60, 95% CI in esophageal adenocarcinoma mortality

31 Secondary outcomes Overall mortality was associated with a 25% reduction in mortality HR 0.75; 95% CI Patients under BE surveillance were more likely to be diagnosed with early stag (stage 0 or stage I) RR 2.11; 95% CI There was no difference between the two groups with regard to receipt of esophagectomy

32 What are the chances? Chandrasoma et al. Am J Surg Pathol cm CLE = 70% chance of BE 3-4cm CLE = 89.5% chance of BE 5 cm CLE = 100% chance of BE Current biopsy protocol 4 quadrant biopsy every 1-2cm of BE Can miss 10-50% of esophageal neoplasms

33 New Techniques for BE, Dysplasia and EAC

34 The Current modes High-definition white light and narrow band imaging Neither allow reliable determination of the presence of intestinal metaplasia or dysplasia within CLE Require biopsies and histological evaluation Without irregular features in the columnar mucosa, biopsies are obtained at random May miss dysplasia or early adenocarcinoma Biopsies take days to process and be read by pathologist

35 Probe-based confocal laser endomicroscopy Confocal endomicroscopy to be used via probes passed down the working channel Real-time assessment of cellular and subcellular architecture within tissue Fixed focal length Depth µm Resolution 1 µm (single RBC) Used in combo w/ IV fluorescein to increase imaging depth (optimal time is 10 min after injection) Distinguish between different epithelial cells and detect dysplasia/neoplasia

36 Miami Criteria (Caillol et al. 2017)

37 Zihni and DeMeester Thor Surg Clin 2018 Squamous Mucosa recognized as light gray, flat, scale like cells Oxyntic gastric mucosa with gastric Pits are round, regular, dark circles

38 Zihni and DeMeester Thor Surg Clin 2018 CLE columnar epithelium w/ regularly spaced glands and cells. Dark Goblet Cells are absent. BE w/ CLE w/ addition of dark round goblet cells. Glands are regular and organized

39 Non dysplastic BE BE with early esophageal Adenocarcinoma

40 P-CLE Evidence Sharma et al Gastroint Endo Prospective RCT 101 BE patient for surveillance or treatment for HGD/EC Bx by HD-WLE/NBI and 4 quadrant random biopsies Bx sites examined by pcle and presumptive dx of tissue was made Blinded pathologist to endocscopic and pcle data Identified an additional 41 areas of HGD-EAC in subjects when lesions visible by WLE were excluded

41 pcle compared to random biopsies during BE surveillance Shah et al endosc Int open Retrospective study pcle identified all cases of EAC in 55 subjects Sensitivity of 67% and specificity of 98% PPV of 67% for HGD-EAC The sensitivity of LGD was low compared to random biopsies Good for real-time use to confirm HGD and EAC, but incremental benefit over WLE/NBI

42 pcle meta-analysis 14 studies, 789 patients, 4047 lesions Per patient Sensitivity 89% Specificity 83% Per lesion Sensitivity 77% Specificity 89% Conclusion: CLE can accurately differentiate neoplasms from nonneoplasms in BE Xiong et al J Gastrentr and hepatol

43 Optical Coherence Tomography and Volumetric Laser Endomicroscopy Optical ultrasonography in which reflected infrared light waves (no sound waves) are used to obtain subsurface, cross-sectional images of mucosal surface Can show mucosal and submucosal structures in microscopic detail The level of detail comes at the price of limited depth Standard endoscope with balloon centered prob Scans 6cm esophagus in 90 seconds Depth of 3mm Manual controller to tag areas of biopsy

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45 Zihni and DeMeester Thor Surg Clin 2018 Squamous mucos on OCT. Uniform layering of esophageal wall. Mucosa, submucosa and 2 layers of the muscularis propria

46 CLE: indicated by loss of normal layering pattern. Mucosa, submucosa and muscularis propria layers are indistinct Dysplasia and cancer by dark appearance to the superficial layers and glandular structures in the subserface layers

47 OCT scoring index: A score > 2 is associated with a sensitivity of 83% and specificity of 75% for dysplasia Trindade and Smith 2016 Ther Adv Gastroenterol

48 Clinical application of VLE Competes with other technologies for screening, surveillance and mapping of BE, dysplasia and EAC NICHE: follow-up of patients after endoscopic resection or ablation therapy No other therapy can image below the neosquamous mucosa to detect buried residual BE glands

49 Swager et al Gastrointest Endosc 17 subjects treated to no visible BE HD-WLE showed no visible lesions VLE showed 1 or more area of subsquamous glandular structure in 13 (76%) The frequency of buried BE was 8%

50 Tsai et al 2012 Gastroint Endosc VLE to predict efficacy of ablation therapy based on the pretreatment thickness of the metaplastic or dysplastic mucosa BE eradication was significantly thinner (257 vs 403 microns) BE thickeness > 333 microns were more likely to have VLE detected residual glands immediately after RFA Se 92% and Sp of 85% They also had increased areas of persistent BE on follow up endoscopy Se 83% and Sp 95%

51 Swager et al Gastroint Endosc 52 EMR 86 VLEhistology matches

52 VLE Next Steps: Swager et al Gastroint Endosc Computer-aided detection of early Barrett s neoplasia using VLE 60 VLE images of ex-vivo VLE-histology correlations BE+/-neoplasia (30/30) Compared to VLE experts who scored the same ex-vivo VLE images the algorithm performed better AUC comparec to 0.81 for experts Tethered swallow capsule (12mm diameter) currently being tested

53 Wide Area Transepithelial Sampling with 3- Dimensional Analysis Brush throught the working channel Bristles are more rigid leading to a deeper tissue sample (lamina propria) Increased stiffness leads to accumulation of clumps of cells on the brush or microbiopsies Asses glandular architecture and therefore dysplasia Sample segmentn lengths up to 6cm with each brush 100,000 cells on each brush -> rolled over on a slide and tip is then placed in formalin for a cell block Second brush is used and placed directly in formalin for cell block Extended depth of field creates a single 3-d image to view the multilayerd sample for the pathologist Neural network-based algorithm identifies the 200 most suspicious cells or clusters

54 Gross et al UEG Non dysplastic BE EAC w/ nuclear pleomorphism, Hyperchromaisa, scant cytoplasm, Loss of cellular cohesion

55 WATS is an adjunct to standard 4 quadrant bx Gross et al united european gastroenterol J. Multicenter prospective trial (25 community based practices) Patients screened for suspected BE and those w/ known BE for surveillance 4204 patients BE 594 cases diagnosed BE with forceps biopsy 493 additional cases were detected using WATS (83% increase) LGD 26 cases by forceps biopsy 23 additional cases by WATS (88% increase)