Risk Stratification of Barrett Esophagus Patients
Risk Stratification of Barrett Esophagus Patients
Objective Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett's oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barrett's Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD.
Design We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC.
Results 293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16–72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively.
Conclusions Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.
Barrett's oesophagus (BO) is the only known precursor to oesophageal adenocarcinoma (OAC) and is defined by replacement of the squamous epithelial lining of the distal oesophagus by columnar epithelium. Although some guidelines do not require the presence of intestinal metaplasia for the diagnosis of BO, most guidelines (eg, from the USA and the UK) require the presence of intestinal metaplasia as a necessary prerequisite for surveillance since previous studies have shown that the risk of malignant progression is considerably lower in BO without intestinal metaplasia. Malignant progression in BO is thought to be a multi-step process, which develops through subsequent grades of dysplasia classified as non-dysplastic BO (NDBO), low-grade dysplasia (LGD) and high-grade dysplasia (HGD) resulting in cancer. Patients with HGD or OAC are offered a therapeutic intervention with either endoscopic therapy or surgery depending on local expertise, patient fitness and depth of invasion. Patients with LGD are considered to have an increased risk of malignant progression over patients with no dysplasia and are offered intensified endoscopic surveillance every 6–12 months or may sometimes undergo endoscopic therapy. For patients with NDBO, current guidelines recommend a 3–5 year surveillance interval. In patients with a diagnosis of indefinite for dysplasia (IND), it is recommended that antireflux therapy is optimised and endoscopy is repeated in 6 months. If subsequent biopsies demonstrate no definite dysplasia, patients should be managed as NDBO.
Currently, surveillance and treatment decisions are solely based on conventional histopathological assessment of surveillance biopsies. Although recent research into objective biological markers for progression is promising, clinical implementation of a biomarker panel is far away and histology is the only risk stratification tool available.
Risk stratification according to dysplasia grade is nevertheless fraught with uncertainty as data on malignant progression rates for LGD are highly diverging, ranging from 0.6% to 13.4% per patient-year. The cause of these variable progression rates is twofold. First, most studies that have investigated progression risk for LGD patients suffer methodological shortcomings. Sample sizes are relatively small, quality of endoscopic follow-up data is limited and several studies were performed in tertiary care settings, resulting in referral bias. However, the most important issue seems to be reliability of the baseline LGD diagnosis. Community pathologists frequently overdiagnose LGD, as previously demonstrated by our group. In that study, a consensus diagnosis by an expert pathology panel could reliably downstage 85% of community LGD diagnoses. In many studies that reported progression rates for LGD patients, expert histological review was not included in the work-up or was only performed in a subset of patients. The lack of a reliable LGD diagnosis in these studies is likely the most important factor associated with the high variability in reported malignant progression rates for LGD patients.
The second important cause for the wide range in reported progression risks is the high interobserver variation between pathologists for diagnosing LGD in BO, even among expert GI pathologists. Most previously reported κ values range from 0.14 to 0.32, which can be classified as poor to fair agreement. Only a minority of studies reported moderate to good agreements between GI pathologists with a special interest in BO, with κ scores ranging from 0.48 to 0.69. Such a wide range in κ values suggests that a reliable LGD diagnosis might be questionable, even for studies that included expert histological review of LGD. The quality and homogeneity of the expert panel seem to be essential in establishing a reliable baseline LGD diagnosis and is important in the interpretation of reported progression risks for patients with LGD.
The Dutch Barrett's Advisory Committee (BAC), founded by the Comprehensive Cancer Centre Amsterdam, is a national consultative working group that offers central pathology review for all Dutch centres.
This retrospective cohort study aimed to establish the prognostic value of the aforementioned expert pathology panel for BO related dysplasia. This was achieved by reviewing histological slides from a large cohort of BO patients with LGD and comparing this review diagnosis to the histological outcome during endoscopic follow-up.
Abstract and Introduction
Abstract
Objective Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett's oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barrett's Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD.
Design We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC.
Results 293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16–72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively.
Conclusions Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.
Introduction
Barrett's oesophagus (BO) is the only known precursor to oesophageal adenocarcinoma (OAC) and is defined by replacement of the squamous epithelial lining of the distal oesophagus by columnar epithelium. Although some guidelines do not require the presence of intestinal metaplasia for the diagnosis of BO, most guidelines (eg, from the USA and the UK) require the presence of intestinal metaplasia as a necessary prerequisite for surveillance since previous studies have shown that the risk of malignant progression is considerably lower in BO without intestinal metaplasia. Malignant progression in BO is thought to be a multi-step process, which develops through subsequent grades of dysplasia classified as non-dysplastic BO (NDBO), low-grade dysplasia (LGD) and high-grade dysplasia (HGD) resulting in cancer. Patients with HGD or OAC are offered a therapeutic intervention with either endoscopic therapy or surgery depending on local expertise, patient fitness and depth of invasion. Patients with LGD are considered to have an increased risk of malignant progression over patients with no dysplasia and are offered intensified endoscopic surveillance every 6–12 months or may sometimes undergo endoscopic therapy. For patients with NDBO, current guidelines recommend a 3–5 year surveillance interval. In patients with a diagnosis of indefinite for dysplasia (IND), it is recommended that antireflux therapy is optimised and endoscopy is repeated in 6 months. If subsequent biopsies demonstrate no definite dysplasia, patients should be managed as NDBO.
Currently, surveillance and treatment decisions are solely based on conventional histopathological assessment of surveillance biopsies. Although recent research into objective biological markers for progression is promising, clinical implementation of a biomarker panel is far away and histology is the only risk stratification tool available.
Risk stratification according to dysplasia grade is nevertheless fraught with uncertainty as data on malignant progression rates for LGD are highly diverging, ranging from 0.6% to 13.4% per patient-year. The cause of these variable progression rates is twofold. First, most studies that have investigated progression risk for LGD patients suffer methodological shortcomings. Sample sizes are relatively small, quality of endoscopic follow-up data is limited and several studies were performed in tertiary care settings, resulting in referral bias. However, the most important issue seems to be reliability of the baseline LGD diagnosis. Community pathologists frequently overdiagnose LGD, as previously demonstrated by our group. In that study, a consensus diagnosis by an expert pathology panel could reliably downstage 85% of community LGD diagnoses. In many studies that reported progression rates for LGD patients, expert histological review was not included in the work-up or was only performed in a subset of patients. The lack of a reliable LGD diagnosis in these studies is likely the most important factor associated with the high variability in reported malignant progression rates for LGD patients.
The second important cause for the wide range in reported progression risks is the high interobserver variation between pathologists for diagnosing LGD in BO, even among expert GI pathologists. Most previously reported κ values range from 0.14 to 0.32, which can be classified as poor to fair agreement. Only a minority of studies reported moderate to good agreements between GI pathologists with a special interest in BO, with κ scores ranging from 0.48 to 0.69. Such a wide range in κ values suggests that a reliable LGD diagnosis might be questionable, even for studies that included expert histological review of LGD. The quality and homogeneity of the expert panel seem to be essential in establishing a reliable baseline LGD diagnosis and is important in the interpretation of reported progression risks for patients with LGD.
The Dutch Barrett's Advisory Committee (BAC), founded by the Comprehensive Cancer Centre Amsterdam, is a national consultative working group that offers central pathology review for all Dutch centres.
This retrospective cohort study aimed to establish the prognostic value of the aforementioned expert pathology panel for BO related dysplasia. This was achieved by reviewing histological slides from a large cohort of BO patients with LGD and comparing this review diagnosis to the histological outcome during endoscopic follow-up.
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