Risk Stratification of Barrett Esophagus Patients
Risk Stratification of Barrett Esophagus Patients
The data analysed in this study were obtained from BO patients who were referred to the BAC. The BAC is a national multidisciplinary consultative working group that harbours pathologists, gastroenterologists and surgeons with extensive experience in management of BO related dysplasia and carcinoma. Upon referral of a patient, the histology slides and endoscopic images are reviewed by expert pathologists and endoscopists, respectively. Subsequently, a multidisciplinary consensus advice on clinical management of the patient is provided.
The histopathological specimens obtained during the initial endoscopic procedure with a diagnosis of LGD by the community hospital pathologist were retrieved and reviewed by the BAC expert pathology panel. This pathology panel consists of six pathologists (FJWtK, GAM, CAS, GJO, MV and SLM) with extensive experience in BO related dysplasia. They have assessed histological inclusion criteria for research studies into various treatments for BO patients performed at the Academic Medical Centre, Amsterdam. At least two panel pathologists were required to review all retrieved H&E stained slides of paraffin embedded biopsy specimens. The presence of intestinal metaplasia was recorded and the presence and degree of dysplasia were classified according to the Vienna classification into NDBO, IND, LGD, HGD or invasive OAC. Histological reviews were performed according to four different methodologies: cases where two pathologists reviewed the specimens together and reached a conclusion (method A); cases that were independently reviewed by two pathologists and where disagreement between pathologists was resolved in a dedicated consensus meeting (method B); cases with two independent expert reviews and where disagreement between both pathologists was resolved after consulting a third panel pathologist (method C); and cases with an initial independent review by three expert pathologists (method D).
The institutional ethics committee of the Academic Medical Centre, Amsterdam has exempted this study from formal ethical review. The follow-up analysis was restricted to all patients who gave written informed consent to the gathering of clinical data.
BO was defined as visible columnar epithelium on initial endoscopy, extending at least 1 cm above the gastro-oesophageal junction, with biopsy specimens showing intestinal metaplasia. All BO patients with LGD who were referred to the BAC between January 2000 and December 2011 were eligible for inclusion. We excluded patients who participated in a previous study by our group on natural history of LGD. Patients who were included in a randomised trial comparing radiofrequency ablation (RFA) with regular endoscopic surveillance in patients with confirmed LGD were also excluded.
Endoscopic follow-up data were analysed in order to relate the review diagnosis to the histological outcome during endoscopic follow-up. For all patients with a referral diagnosis of LGD, follow-up endoscopic procedures with biopsies were identified in the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA database). The PALGA database has nationwide coverage since 1991, archiving the reports of all pathology laboratories in the Netherlands. Subsequently, one investigator visited the regional referring hospitals to collect all follow-up endoscopy and pathology reports. Data on endoscopic follow-up were entered in a dedicated database and included patient demographics (age, gender, hospital of origin), endoscopic results (procedure date, oesophageal landmarks, number of biopsies taken) and histological diagnosis.
Duration of follow-up was calculated for each patient from the date of referral LGD endoscopy to the most recent endoscopic procedure with biopsies.
Primary endpoint of the study was development of any malignant progression (HGD/OAC) during endoscopic follow-up. If a patient reached the endpoint of the study, the histological slides from the HGD/OAC diagnosis had to be confirmed by the BAC expert pathology panel according to the aforementioned criteria. Pathologists were blinded for their previous review results.
Secondary endpoint of the study was the interobserver agreement between the members of the expert pathology panel.
Mean and SD were used for normally distributed continuous variables. Median and IQR were used for continuous variables with a skewed distribution. Kaplan–Meier survival analysis was performed to estimate the cumulative risk of progression to HGD/OAC. Time to progression was calculated as the interval between date of referral LGD endoscopy and date of first endoscopy with biopsies demonstrating HGD/OAC. Follow-up data were censored at the time of first event or latest known follow-up. Differences in cumulative risk between different review diagnosis subgroups were compared using the log-rank statistic. All reported p values were two-tailed and p values <0.05 were considered to indicate statistical significance.
All cases with expert histological review according to method B, and the two initial readings for cases that were reviewed according to method C were included in the analysis of interobserver agreement. Interobserver agreement between the first and second ratings was assessed using Cohen's (weighted) κ. Strength of agreement was categorised as follows: 0.00–0.20, poor; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, good; and 0.81–1.00, very good.
Statistical calculations were performed using the Statistical Package for the Social Sciences (SPSS 20.0, IBM Corp., Armonk, New York, USA).
Methods
Setting and Source Population
The data analysed in this study were obtained from BO patients who were referred to the BAC. The BAC is a national multidisciplinary consultative working group that harbours pathologists, gastroenterologists and surgeons with extensive experience in management of BO related dysplasia and carcinoma. Upon referral of a patient, the histology slides and endoscopic images are reviewed by expert pathologists and endoscopists, respectively. Subsequently, a multidisciplinary consensus advice on clinical management of the patient is provided.
The histopathological specimens obtained during the initial endoscopic procedure with a diagnosis of LGD by the community hospital pathologist were retrieved and reviewed by the BAC expert pathology panel. This pathology panel consists of six pathologists (FJWtK, GAM, CAS, GJO, MV and SLM) with extensive experience in BO related dysplasia. They have assessed histological inclusion criteria for research studies into various treatments for BO patients performed at the Academic Medical Centre, Amsterdam. At least two panel pathologists were required to review all retrieved H&E stained slides of paraffin embedded biopsy specimens. The presence of intestinal metaplasia was recorded and the presence and degree of dysplasia were classified according to the Vienna classification into NDBO, IND, LGD, HGD or invasive OAC. Histological reviews were performed according to four different methodologies: cases where two pathologists reviewed the specimens together and reached a conclusion (method A); cases that were independently reviewed by two pathologists and where disagreement between pathologists was resolved in a dedicated consensus meeting (method B); cases with two independent expert reviews and where disagreement between both pathologists was resolved after consulting a third panel pathologist (method C); and cases with an initial independent review by three expert pathologists (method D).
The institutional ethics committee of the Academic Medical Centre, Amsterdam has exempted this study from formal ethical review. The follow-up analysis was restricted to all patients who gave written informed consent to the gathering of clinical data.
Study Population
BO was defined as visible columnar epithelium on initial endoscopy, extending at least 1 cm above the gastro-oesophageal junction, with biopsy specimens showing intestinal metaplasia. All BO patients with LGD who were referred to the BAC between January 2000 and December 2011 were eligible for inclusion. We excluded patients who participated in a previous study by our group on natural history of LGD. Patients who were included in a randomised trial comparing radiofrequency ablation (RFA) with regular endoscopic surveillance in patients with confirmed LGD were also excluded.
Endoscopic Follow-up
Endoscopic follow-up data were analysed in order to relate the review diagnosis to the histological outcome during endoscopic follow-up. For all patients with a referral diagnosis of LGD, follow-up endoscopic procedures with biopsies were identified in the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA database). The PALGA database has nationwide coverage since 1991, archiving the reports of all pathology laboratories in the Netherlands. Subsequently, one investigator visited the regional referring hospitals to collect all follow-up endoscopy and pathology reports. Data on endoscopic follow-up were entered in a dedicated database and included patient demographics (age, gender, hospital of origin), endoscopic results (procedure date, oesophageal landmarks, number of biopsies taken) and histological diagnosis.
Duration of follow-up was calculated for each patient from the date of referral LGD endoscopy to the most recent endoscopic procedure with biopsies.
Study Endpoints
Primary endpoint of the study was development of any malignant progression (HGD/OAC) during endoscopic follow-up. If a patient reached the endpoint of the study, the histological slides from the HGD/OAC diagnosis had to be confirmed by the BAC expert pathology panel according to the aforementioned criteria. Pathologists were blinded for their previous review results.
Secondary endpoint of the study was the interobserver agreement between the members of the expert pathology panel.
Statistical Analysis
Mean and SD were used for normally distributed continuous variables. Median and IQR were used for continuous variables with a skewed distribution. Kaplan–Meier survival analysis was performed to estimate the cumulative risk of progression to HGD/OAC. Time to progression was calculated as the interval between date of referral LGD endoscopy and date of first endoscopy with biopsies demonstrating HGD/OAC. Follow-up data were censored at the time of first event or latest known follow-up. Differences in cumulative risk between different review diagnosis subgroups were compared using the log-rank statistic. All reported p values were two-tailed and p values <0.05 were considered to indicate statistical significance.
All cases with expert histological review according to method B, and the two initial readings for cases that were reviewed according to method C were included in the analysis of interobserver agreement. Interobserver agreement between the first and second ratings was assessed using Cohen's (weighted) κ. Strength of agreement was categorised as follows: 0.00–0.20, poor; 0.21–0.40, fair; 0.41–0.60, moderate; 0.61–0.80, good; and 0.81–1.00, very good.
Statistical calculations were performed using the Statistical Package for the Social Sciences (SPSS 20.0, IBM Corp., Armonk, New York, USA).
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