Barrett s Esophagus: Review of Diagnostic Issues and Pre- Neoplastic Lesions

Transcription

1 Barrett s Esophagus: Review of Diagnostic Issues and Pre- Neoplastic Lesions Robert Odze, MD, FRCPC Chief, Gastrointestinal Pathology Associate Professor of Pathology Brigham and Women s Hospital Harvard Medical School Boston, MA

2 Barrett s Esophagus: Metaplasia and Dysplasia Metaplasia - Def n/types - Pathogenesis - Differential Diagnosis Dysplasia - Incidence/risk factors - Pathologic features - Adjunctive Diagnostic tests - Natural History - Treatment

3 Barrett s Esophagus Definition Columnar metaplasia of esophageal squamous epithelium (any length) Recognized at endoscopy Goblet cell metaplasia

4 Barrett s Esophagus Gross Types Long segment (>3cm) Short segment (1-3cm) Ultrashort segment (0-1cm)

5 Barrett s Esophagus Epithelial Types Intestinal ( specialized ) type (99%>2cm) Cardia type ( junctional ) Fundic type

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8 Short (Ultrashort ) BE vs. Chronic Carditis Distinction important Different clinical, etiologic, pathologic, outcome, risk of malignancy

9 Summary of Factors That Impede the Ability to Separate the True Gastric Cardia from the Distal Esophagus at Endoscopy Hiatal Hernia (which causes obliteration of the proximal gastric folds) Irregular Z line Erosions in Distal Esophagus (which mimicks BE) Respiratory Movements Sampling Error Similar Histology

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16 Table 1. Frequency of significant morphologic parameters in biopsies from patients with BE or CIM Disease Squamous Crypt Crypt Incomplete Diffuse IM HG MEP EG/ED Category over IM Disarray Atrophy IM (>50%) BE 8/14 17/20 12/20 20/20 12/20 8/20 14/20 6/20 (%) CIM 0/7 10/20 5/20 10/20 2/20 0/20 3/20 0/20 (%) P value < BE: Barrett s esophagus; CIM: carditis with intestinal metaplasia; IM: intestinal metaplasia; MEP: Multilayered epithelium; HG: Hybrid glands; EG/ED: esophageal glands/ducts

17 Mucin Histochemistry Stain Esoph Cardia Goblet Non-Goblet Goblet Non-Goblet Alcian blue (acid mucin High Iron diamine (sulphomucin)

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21 Multilayered Epithelium 1. Hybrid epithelium (squam/colum) - EM, cytokeratins 2. Biologically active 3. Phenotypically similar to Barrett s Esophagus 4. Highly associated with Barrett s esophagus and GERD

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24 Esophageal versus Cardia Intestinal Metaplasia Feature Esophagus IM Cardia IM (BE) 1. GERD clinical profile Irregular Z line Esophagitis (histologic) Gastritis (histologic) H. Pylori Eosinophils Neut, Plasma, Lymphocytes Multilayered epithelium HID stain positive MUC 1, 6 positive BE CK 7/20 pattern + +/- 12. Complete > incomplete IM - +

25 Barrett s Esophagus Dysplasia: Definition Neoplastic epithelium that remains confined within the basement membrane not reactive not synonymous with atypical unlikely to spontaneously regress Both a marker and a precursor of adenocarcinoma

26 Barrett s Dysplasia/Carcinoma Risk Prevalence : 6-8% Incidence : 0.2 3% (1/52 1/208 patient years) Relative Risk: x

27 Incidence Rate of Adenocarcinoma in Barrett s Esophagus Incidence Follow-up Series Patients Cases (Patient Incidence (No.) (No) Years) Rate Haammeeteman et al /52 Bonelli et al /55 Roberston et al /56 Miros et al /96 Iftikhar et al /115 Drewitz et al /208 O Connor et al /285 Sepchler et al /259 Sharma et al /212

28 Barrett s Dysplasia/Carcinoma Risk Factors Length of BE Severity of Reflux Hiatus Hernia size Gender Ethnicity Age Smoking? Alcohol?

29 Patient Characteristics Variable GERD Barrett s HGD/CA (N=2170) (N=1189) (N=131) Male sex 98% 99% 99% Age (yr*) White ethnicity 76% 83% 89% Ethanol Consumption 40% 37% 42% Smoking 34% 25% 27% Hiatal hernia 24% 65% 84% Hiatal hernia size (cm*) Barrett s length (cm*) Avidan et al. Am J Gastroenterol2002;97(8)

30 Dysplasia Pathologic Features 1. Gross - Flat - Elevated (plaque, nodule, polyp) 2. Microscopic - Adenoma-like - Non-adenoma like

31 Dysplasia in the GI Tract Negative Indefinite Positive (low, high) Intramucosal AdenoCa Submucosal (Invasive) AdenoCa

32 Vienna System and Dysplasia Morphology Study Group Classification of Dysplasia in IBD Vienna DMSG 1. Negative for neoplasia/dysplasia Negative for dysplasia 2. Indefinite for neoplasia/dysplasia Indefinite for dysplasia 3. Non-invasive low-grade neoplasia Low-grade dysplasia (low-grade adenoma/dysplasia) 4. Non-invasive high-grade neoplasia High-grade dysplasia 4.1 High-grade adenoma/dysplasia 4.2 Non-invasive carcinoma (carcinoma in situ) 4.3 Suspicious of invasive carcinoma 5. Invasive Neoplasia Adenocarcinoma* 5.1 Intramucosal Adenocarcinoma Intramucosal 5.2 Submucosal carcinoma or beyond Invasive *not described by DMSG

33 Non-Recommended Terms Atypia Adenomatous Changes Carcinoma in Situ

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54 Crypt Dysplasia with surface maturation. A clinical, pathologic and molecular study of a Barrett s Cohort L. Lomo, P. Blount, R. Sanchez, P. Galipeau, D. Cowan, D. Ayub, P. Rabinovitch, B. Reid, R. Odze Am J Surg Pathol (In Press)

55 Pathologic Features of the Study Cohort (N=206) Feature BCDA Controls (N=15) (N=191) p value Maximum diagnosis Associated neoplasia (total) 13/15 (87%) 112/191 (59%) Low-grade dysplasia 2/15 (13%) 70/191 (37%) 0.09 High-grade dysplasia 8/15 (53%) 35/191 (18%) Adenocarcinoma 3/15 (20%) 7/191 (4%) 0.03

56 Summary of Molecular Biomarkers of the Study Cohort Feature BCDA Controls (N=15) (N=191) p value > 1 Molecular abnormality 12/15 (80%) 100/191 (52%) p LOH 8/9 (89%) 67/116 (58%) p LOH 4/9 (44%) 12/116 (10%) 0.016?4N 2/15 (13%) 11/191 (5.8%) 0.24 Aneuploidy 5/15 (33%) 12/191 (6.3%) Any flow abnormality 6/15 (40%) 15/191 (7.9%) 0.001

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64 Barrett s Esophagus Feature Regeneration Dysplasia Inflammation ++ +/- Ulceration ++ +/- Surface Maturation + - Pleomorphism - +/- Loss of Polarity - +/- Atypical Mitoses - +/- Surface Proliferation +/- ++ Villiform Change +- +/- Mucin Depletion +/- ++

65 Barrett s-related Dysplasia Interobserver Agreement Category % agreement HGD + IMC vs. others 85-87% Negative vs. others 71-72% Negative + Ind vs. others 75-77% Neg vs. Ind/LGD vs. HGD/IMC 58-61% Reid BJ et al. Hum Pathol 1988

66 Barrett s-related Dysplasia Interobserver Variation Category Set 1 Set 2 No dysplasia 0.44 (mod) 0.58 Indefinite 0.13 (slight) 0.15 Low grade 0/23 (fair) 0.31 High grade/cancer 0.63 (substantial) 0.64 Montgomery EA et al. Hum Pathol 2001

67 Adjunctive Techniques Proliferation Markers DNA content (aneuploidy) Telomerase Genetic mutations (p53, p16, Kras, APC, B catenin) Growth Factors Apoptosis Inhibitors Cyclooxygenase 2

68 p53 in Negative/ Indefinite Mucosa

69 AMACR Immunostaining is Useful in Detecting Dysplastic Epithelium in BE, UC and CD R Dorer, J Glickman, RD Odze Am J Surg Pathol (In Press)

70 Dorer et al Results AMACR Positive Dysplasia BE UC/CD Negative 0% 0% Indefinite 21% 14% Low Grade 38% 96% High Grade 81% 80% AdenoCa 72% 71%

71 A B C Figure 2. AMACR expression in colitis without dysplasia (A), with high-grade dysplasia (B), and invasive adenocarcinoma (C).

72 Natural History Dysplasia (%) n Cancer (%) None (2) Low grade 72 5 (7) High grade (22) Sampliner. Am J Gastroenterol 2002:97(8);

73 Esophagectomy for High-Grade Dysplasia Series Unsuspected Carcinoma Edwards (1996) 8/11 (73%) Heimiller (1996) 13/30 (43%) Cameron (1997) 2/19 (10.5%) Ferguson (1997) 8/15 (53%) Falk (1997) 4/12 (33%) Total 35/87 (40%)

74 Natural History of High-Grade Dysplasia Prospective Studies Proportion with Cancer Seattle (Baseline HGD) N=76 Kansas VA, N=15 Seattle (Incident HGD) N=27 Hines VA, N=75 (Excluded 4 cancers in 1 st year) Years Schnell et al, Gastroenterol 2001; 120: Reid et al, Am J Gastroenterol 2000; 95: Weston et al, Am J Gastroenterol 2000; 95:

75 Low-Grade Dysplasia Prospective Studies Study No. LGD Progress to Cancer (%) Regression (%) Weston et al (2%) 31 (65%) Schnell et al (3%) ND Sharma et al. Conio et al (3%) 1 (6%) 103 (66%) 12 (75%) Weston et al, Am J. Gastroenterol 2001; 96: Schnell et al, Gastroenterology 2001; 120: Sharma et al, Gastroenterology 2002; 122:A20 Conio et al, Am J Gastroenterol 2003;

76 Management Controversial Varies between institutions Dependent on surveillance techniques

77 ACG guidelines for Surveillance in Barrett s esophagus: (Sampliner et al, Am J Gastroenterol 97:1888,2002) Chronic GERD Symptoms Screening Endoscopy with Biopsies Negative for dysplasia Low grade dysplasia High-grade dysplasia x2 endoscopies Repeat endoscopy with biopsy Expert pathologist opinion 3 year surveillance Repeat x 1 Focal Mucosal Multifocal Annual surveillance irregularity Until no dysplasia 3 months Intervention surveillance EMR (surgical)

78 The Case for Barrett s Surveillance 5-year Survival of Surveyed and Non-surveyed Cases 100% 90% 90.0% 80% 73.3% 70% 5-year Survival 60% 50% 40% 30% 20% 52.9% 20.0% 20.0% Surveyed cases Non-surveyed cases 10% 0% 0.0% Corley Streitz Peters Corley et al, Gastroenterology 2002; 122:633 Streitz et al, J Thorac Cardiovasc Surg 1993; 105:383 Peters et al, J Thorac Cardiovasc Surg 1994; 108:813

79 Ideal Biopsy Protocol Jumbo forceps 4 quadrant Q2 cm in BE 4 quadrant Q1 cm in dysplasia All nodules/polyps/masses Confirm with experienced GI pathologist

80 Management Considerations Surveillance vs. Esophagectomy Extent of HGD Extent of LGD Nodularity Patient age Comorbidities Length of BE

81 Extent of dysplasia in BE Buttar et al, Gastro 2001;120: # 1 year 3 year RR Patients survival survival Carcinoma Cancer Focal HGD 33 93% 86% 12% - Diffuse HGD* 67 62% 66% 42% 5.36 Nodularity % 3.98 Lack of acid suppression % 2.48 Focal <5 crypts, diffuse >5 crypts or >1 biopsy

82 Extent of Low Grade Dysplasia is a Significant Risk Factor for Cancer in Barrett s Esophagus Odze et al, Mod Pathol 2005;18(1):119

83 Table 3: Mean number of crypts/biopsy in each diagnostic category Maximum Diagnosis Non-Progressors Progressors Negative for dysplasia (range; SD) ( ; 9.51) ( ; 9.07) Indefinite for dysplasia (range; SD) ( ; ( ; 0.088) LGD (range; SD ( ; 4.98) ( ; 6.25) HGD (range; SD) ( ; 2.27) ( ; 2.4)

84 Flow Cytometry: Prospective Studies Patients without High-Grade Dysplasia Probability of Cancer Reid et al N=247 patients ½ biopsy every 2 cm Aneuploid and/or 4N 28% 0% p < Diploid, normal 4N Normal Cytometry (N=17) Teodori et al N=30 patients Abnormal Cytometry (N=13) 0% cancer 23% cancer p<0.01 for dysplasia or cancer (46% Reid et al, Am J Gastro 2000; 95:1669 Teodori et al, Cytometry 1998; 34:254

85 Ulcers in BE (Montgomery et al, Am J Gastro 2002;97(11):27-31) Ulcer-related Dysplasia # cases Ulcers CA on Grade (35/138) follow-up Neg 44 7% 0% Indef 22 9% 0% LGD 26 0% 0% HGD 33 33% 8/10 (80%)* CA 13 54% - *8/10 vs 12/23 p<.05

86 Barrett s Esophagus: New Surveillance Strategies Balloon cytology Fluorescence spectroscopy Chromoendoscopy Flow cytometry

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