Overdiagnosis of high-grade dysplasia in Barrett's esophagus: a multicenter, international study

Abstract

Numerous histological mimics of high-grade dysplasia in Barrett's esophagus predispose to overdiagnosis and potential serious mismanagement, including unnecessary esophagectomy. This study investigates the prevalence and sources of this problem. Biopsies from 485 patients diagnosed with Barrett's high-grade dysplasia were screened for a multi-institutional, international Barrett's endoscopic ablation trial. Screening included review of the original diagnostic slides and an additional protocol endoscopy with an extensive biopsy sampling. Observer variability by the study pathologists was assessed through two blinded diagnostic rounds on 437 biopsies from 26 random study endoscopies. Study diagnostic reassessments revealed significantly lower rates of high-grade dysplasia. Only 248 patients (51%) were confirmed to have high-grade dysplasia. The remaining patients had inflamed gastric cardia without Barrett's (n ¼ 18; 7%), Barrett's without dysplasia (n ¼ 35; 15%), indefinite change (n ¼ 61; 26%), low-grade dysplasia (n ¼ 79; 33%), adenocarcinoma (n ¼ 43; 18%), and other (n ¼ 1; o1%), yielding an alarming total of 194 or 40% of patients who were overdiagnosed with Barrett's highgrade dysplasia. Study pathologists achieved a high-level agreement (90% three-way inter-observer agreement per biopsy, Kappa value 0.77) for high-grade dysplasia. Confounding factors promoting overdiagnosis included Barrett's inflammatory atypia (n ¼ 182), atypia limited to the basal metaplastic glands (n ¼ 147), imprecise criteria for low grade neoplasia (n ¼ 102), tangential sectioning artifact (n ¼ 59), and reactive gastric cardiac mucosa (n ¼ 38). A total of 194 patients (40%) were overdiagnosed with Barrett's high-grade dysplasia, as affirmed by the extensive screening process and high-level study pathologist agreement. The multiple diagnostic pitfalls uncovered should help raise pathologists' awareness of this problem and improve diagnostic accuracy.

The importance of a second opinion in the diagnosis of Barrett’s esophagus: a “real life” study

“…This study, carried out in real life conditions (i.e., outside formal research trials), once again highlights the problem of biopsy interpretation in BE, not limited to the identification of dysplasia. In fact, the level of discrepancy we found in our series (78%) suggests that in the daily routine, this issue may be even more worrisome than thought based on the data inferred by research trials (18-21), even though two recent studies on consistent cohorts of patients showed that only 27% of the initial diagnoses of LGD and 51% of those of high-grade dysplasia were confirmed after a second opinion by experienced pathologists (26,27). With regard to the classification of dysplasia, there are several objective reasons that make it sometimes difficult for the pathologist to provide an accurate grading: when erosion, ulcerations, or active inflammation is present, regenerating Barrett's epithelium may feature cytologic aspects resembling dysplasia (28); in addition, biopsies may be poorly oriented or have artifacts, thus limiting an accurate evaluation of dysplasia that may be present.…”

Diagnosis and risk stratification of Barrett’s dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue

“…Although an excellent interobserver agreement for HGD has been reported among GI pathologists,13 14 one recent study demonstrated that on review of 485 HGD samples from both academic and private centres by experienced GI pathologists, up to 40% were overdiagnosed with HGD and had to be reinterpreted as LGD, IND, ND or no BO 16. In this regard, abnormal flow cytometric results may serve as objective evidence to confirm a morphological impression or suspicion of HGD.…”

p53 protein accumulation predicts malignant progression in Barrett's metaplasia: a prospective study of 275 patients

“…3,9 Unfortunately, the cornerstone of surveillance programmes, dysplasia grading, suffers from significant variation in reproducibility, even among experts in gastrointestinal pathology. Pathologists in general practice were found to have even more problems with dysplasia grading in BM, 19,20 and it has been recommended that the grade of dysplasia be confirmed by an expert pathologist. 3 We previously proposed that p53 protein accumulation in biopsies from patients with BM, detected by IHC staining, is a predictor of malignant progression.…”