Progression to cancer in patients with confirmed dysplasia compared to dysplasia downgraded to non-dysplastic metaplasia in Barrett’s esophagus: a retrospective cohort study in Sweden

Article information

Clin Endosc. 2024;57(6):768-774
Publication date (electronic) : 2024 November 25
doi : https://doi.org/10.5946/ce.2023.313
1Department of Upper Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden
2Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
3Synlab AB Täby, Stockholm, Sweden
4Deceased, formerly at the Department of Pathology Karlskrona Hospital, Karlskrona, Sweden
5Department of Clinical Sciences, Danderyds Hospital, Karolinska Institutet and Department of Surgery, Ersta Hospital, Stockholm, Sweden
Correspondence: Peter Elbe Department of Upper Digestive Diseases, Karolinska University Hospital, Hälsovägen 11, Stockholm 14186, Sweden E-mail: peter.elbe@regionstockholm.se
Received 2023 December 22; Revised 2024 June 14; Accepted 2024 July 1.

Abstract

Background/Aims

This study aimed to clarify the risk of progression in patients with non-dysplastic Barrett’s esophagus (NDBE) and patients with confirmed low-grade dysplasia (LGD) and indefinite for dysplasia (IND) after an expert pathologist review of patients with BE with suspected dysplasia in a prospective cohort.

Methods

Patients with Barrett’s esophagus diagnosed with dysplasia at Ersta Hospital in Stockholm from 1998 to 2012 were included. The first dysplastic specimen in all patients was re-evaluated by two expert pathologists and classified as NDBE, LGD, IND, or cancer, including high-grade dysplasia. The incidence rates (IRs) and IR ratios were calculated with 95% confidence intervals.

Results

Of 423 patients with Barrett’s esophagus with dysplasia, 266 (62.9%) were re-classified as NDBE, 83 (19.6%) had LGD, 71 (16.8%) had IND, and 3 (0.7%) patients had cancer. During the follow-up, 34 (8%) patients developed cancer, most of them within five years, while others progressed after up to 25 years of surveillance. IRs for cancer among patients with NDBE was 0.41%/year compared to 1.84%/year for LGD (p<0.001) and 1.43%/year for IND (p=0.008).

Conclusions

Long-term risk of progression to cancer did not differ between patients with confirmed LGD and IND. These findings suggest that patients with IND should undergo similar management as patients with LGD.

Graphical abstract

INTRODUCTION

Barrett’s esophagus (BE) is a metaplasia of the normal squamous cell-lined epithelium in the distal esophagus due to chronic gastroesophageal reflux and is a known risk factor of progression to esophageal adenocarcinoma.1 The incidence of esophageal adenocarcinoma has increased dramatically in the Western world since the 1970s and is now also increasing in other parts of the world.2 This increase is expected to be exacerbated by poor lifestyle factors, above all increasing rates of obesity.3 BE is the only known precursor to esophageal adenocarcinoma, and is the reason why patients with BE are usually recommended to be included in an endoscopic surveillance program, in order to detect dysplasia or cancer lesions at an early stage.4

The development of endoscopic treatment techniques has provided an opportunity for the organ preserving treatment of dysplastic and early cancer lesions in patients who previously had to undergo esophageal resection. Endoscopic techniques have become gold standard treatment of early esophageal cancer and dysplastic lesions.5-9

For many years, patients with low-grade dysplasia (LGD) were not considered to have a particularly high risk of developing cancer. Therefore, these patients were monitored through follow-ups until they developed high-grade dysplasia (HGD), which often necessitated esophagectomy. However, the interobserver variability of dysplastic BE specimens is high, even among gastrointestinal specialized pathologists.10 Therefore, it has become standard procedure that all dysplastic specimens are re-evaluated by an expert. Verified LGD has been shown to have up to a 26.5% risk of progressing to cancer.11 Today, all major guidelines recommend that ablation should be offered to all patients with BE with verified LGD but without visible lesions, although some guidelines recommend that LGD should be verified on two consecutive occasions before ablation is perfomed.5,6

The diagnosis of indefinite for dysplasia (IND) is used when a pathologist is uncertain of whether the specimen is dysplastic or not. At present, the management of IND remains a topic of debate and there is no consensus in different guidelines.12

The aim of this study was to evaluate the long-term risk of developing cancer in patients with BE after an expert pathologist re-evaluation of all patients with a primary diagnosis of dysplastic BE.

METHODS

Study design and population

We conducted a cohort study including patients undergoing BE surveillance at Ersta Hospital from 1998 to 2012. All patients diagnosed with dysplasia were included and had their first dysplastic specimen re-evaluated by two expert gastrointestinal pathologists (A.O. and L.M.) who were blinded to all clinical information. Patients whose first dysplastic specimen was re-evaluated as cancer (including cancer in situ and HGD) were excluded from further analysis. The remaining patients were assigned an index date defined as the date of detection of the primary dysplastic specimen. Patients were followed until a diagnosis of cancer, end of study, or death, whichever came first. The primary outcome was progression to cancer.

Since some patients were followed since the 1990s, the follow-up protocol was revised during the course of the study. In the 1990s there were no implemented guidelines, and the Prague Classification was not yet created. Thus, in the first years of the registry, clinical management was usually decided by the endoscopist. As the international and national guidelines developed, the follow-up became more structured according to the guidelines.

Clinical data used in this study included age, sex, length of BE, dates of first and last gastroscopy, date of diagnosis of any dysplasia or cancer, date and type of treatment, and date of death.

Biopsy management and review

Biopsies were originally fixed in formalin and stained with hematoxylin and eosin. In some cases, staining for Alcian blue and periodic acid-Schiff to detect intestinal metaplasia was also performed. The original assessments were performed by ten different pathologists, none of whom was a specialized gastrointestinal pathologist. The primary pathology report graded dysplasia in three grades using the systematized nomenclature of medicine (SNOMED) system13: grade 1, slight grade of dysplasia (SNOMED code M69726); grade 2, moderate grade of dysplasia (SNOMED code M69727); grade 3, severe grade of dysplasia (SNOMED code M69728). Later, grades 1 and 2 have been defined as LGD, and grade 3 as HGD. The pathological review in this study was performed using the Vienna classification for dysplasia in BE and classified the specimens as HGD, LGD, IND, or non-dysplastic BE (NDBE) as proposed by Schlemper et al.14 After an individual review by the two pathologists, a consensus diagnosis was agreed upon in all patients. Immunohistochemistry was used in some patients, but during the review of the specimens this added nothing to the assessment of dysplasia and was not included in the study.

Statistical analysis

Time at risk of developing cancer for each patient was defined as the time between the index date and the date of endoscopy with a finding of cancer (including HGD), or the last preceding gastroscopy before withdrawal, death, or the end of the study period, whichever came first. The incidence rate (IR) was calculated by dividing the number of cancer cases of each subgroup by the number of follow-up years of the subgroup. The relative risks were estimated by calculating the incidence rate ratio (IRR) with 95% confidence intervals (CIs). The cohort was stratified to calculate incidences and relative risks within each stratum. Statistical calculations were made using Stata IC 16.1 software (StataCorp.).

Ethical statements

This study was approved by the ethics committee in Stockholm (Dnr: 2009/1196-31/1).

RESULTS

In total, 1,180 patients were identified in the study population in the BE database, of which 455 (38.6%) patients had a primary diagnosis of dysplasia. Thirty-two patients were excluded due to misclassification, previous esophageal cancer, double registration, or because the specimen could not be retrieved for review. A total of 423 patients were eligible for re-evaluation and included in the study (Fig. 1).

Fig. 1.

Inclusion of study patients with Barrett’s esophagus.

Figure 2 shows the results of the expert pathologist review where 266 (62.9%) patients were downgraded from dysplasia to NDBE, 71 (16.8%) were re-evaluated as IND, and 82 (19.6%) patients as LGD. Three (0.7%) patients were found to have cancer in the first reviewed specimens and were excluded from further analysis, while the remaining 420 patients were included in the follow-up. All reviewed patients had confirmed BE. Table 1 shows patient characteristics stratified by dysplasia grade before and after an expert pathologist review. As expected, most of the included patients were men (71.9%), the median age was 58 years, and the average BE length was 3.7 cm.

Fig. 2.

Original diagnoses and diagnoses after a review of the biopsies from Barrett’s esophagus.

Patient characteristics stratified by diagnosis before and after an expert pathologist review of patients with Barrett’s esophagus

Risk of progression to cancer during follow-up

The median follow-up time in the study was 12 years (interquartile range, 7–16 years), although some patients were followed for more than 26 years. The total follow-up time was 4,593 person-years. During the follow-up period, 34 (8.1%) patients developed cancer.

The annual IR for cancer for the entire cohort was 0.87% (95% CI, 0.62%–1.22%). For patients with NDBE after expert review, the IR was 0.41% (95% CI, 0.22%–0.77%) compared to 1.43% (95% CI, 0.77%–2.66%) for IND and 1.84 (95% CI, 1.09–3.10) for LGD. The IRR comparing IND to NDBE was 3.47 (95% CI, 1.30–9.29, p=0.008), and 4.46 (95% CI, 1.84–11.23, p<0.001) comparing LGD to NDBE (Table 2). The risk of progression increased by 20% per cm of BE length. Four patients (one with NDBE, two with IND, and one with LGD) developed cancer more than 20 years after their initial BE diagnosis. The number of cancer cases in relation to the number of years with Barrett's diagnosis is shown in Figure 3.

Annual incidence rate for developing cancer and incidence rate ratios in patients with Barrett’s esophagus

Fig. 3.

Time to cancer during follow-up of patients with Barrett’s esophagus.

DISCUSSION

In the current study more than 60% of the patients primarily diagnosed with BE dysplasia were downgraded by expert pathologists to NDBE, 20% had confirmed LGD, and almost 20% were diagnosed with IND. Thus, the re-evaluation changed the diagnosis in the majority of patients, which has a significant impact on treatment and follow-up. Patients with confirmed LGD had a more than a four-fold increased risk of cancer compared to patients who were downgraded to NDBE. The risk of developing cancer did not differ between patients considered to have IND and patients with LGD, suggesting that the former group of patients needs to be considered for surveillance and treatment in the same way as patients with LGD in the future.

It would have been interesting to analyse the association between segment length and the degree of dysplasia regarding the risk of cancer progression. However, in the current study, the sample size was too small to make subanalyses possible.

The finding that an expert pathologist re-evaluation of BE dysplasia results in a substantial downgrading of dysplasia is in agreement with the findings of several previous studies and confirms that a second opinion is important.10,11 It has previously been shown that re-evaluation can discriminate cancer risk, reporting similar incidences for NDBE and LGD as was shown in this study for downgraded NDBE and confirmed dysplasia. The high risk of progression among patients with confirmed LGD has made pathological re-evaluation the standard of care.10 Furthermore, the high risk among these patients has called for treatment before the development of cancer. Endoscopic radiofrequency ablation (RFA) of LGD has been shown to successfully reduce the risk of progression to cancer.11 However, the diagnosis of LGD is difficult and there is a high degree of interobserver variability between pathologists, even among gastrointestinal expert pathologists. Skacel et al.15 found that if two pathologists agreed on LGD, 41% of patients progressed to cancer, and if all three pathologists agreed, then 80% of the patients progressed. Further research is needed to increase the accuracy of BE dysplasia evaluation.

According to the Vienna classification, IND is used when there is uncertainty about the real nature of the lesion.16 As for LGD, IND is a subjective diagnosis with low interobserver agreement. A recent study conducted in the UK reported that p53 can be used to improve the accuracy of the diagnosis and can reduce the rate of IND; however, there was no consensus regarding the risk of progression and how patients with IND should be managed. The risk of progression to cancer for IND found in this study was in the same range as that reported in a recent meta-analysis.17 The yearly risk of cancer among patients with IND was not significantly different from that of patients with LGD. Since very few patients present with IND on repeat endoscopies, it has been argued that patients with IND should be kept on endoscopic surveillance until the patient either presents with LGD or NDBE.18 Several guidelines do not address the management of IND, while others argue that IND should be considered NDBE if the IND cannot be confirmed at a second endoscopy.12 Since this study and recent reports indicate that IND has a similar risk of progression to cancer as LGD, future guidelines on surveillance and treatment recommendations for this clinical group may need to be updated.

The risk of progression to cancer in the current study was found to increase with the length of the Barrett segment, in agreement to previous studies.19 Another important finding is that some patients were found to progress to cancer after up to 20 years of follow-up, which also has implications for future surveillance.

This study has some limitations that should be acknowledged. Firstly, only the first specimens on each individual patient where dysplasia had been reported were reviewed. It would have been an advantage if all the dysplastic specimens in the study had been reviewed, or at least the specimens from endoscopies after LGD confirmation, since this is what is recommended in some of the international guidelines today.5,6 Secondly, patients with BE in the cohort who were never diagnosed with dysplasia were not included in the study. This could have added cancer IRs for also this group. There are data to suggest that even minor esophageal anomalies, such as reactive changes that the downgraded patients are assumed to have, may confer a somewhat elevated cancer risk.20 Although a type 2-error could not be ruled out, patients that had their BE downgraded to NDBE in this study did not appear to have an elevated cancer risk compared to other groups of patients with NDBE.4 Although it would have been interesting to compare the incidence of IND before and after review, the non-expert pathologists did not use IND in their assessment, meaning that we were unable to make this comparison. Another limitation is that despite the fact that Ersta Hospital has one of Sweden’s largest databases of patients with BE, most of their gastroscopies have not been performed by endoscopists specialized in BE. Thus, several endoscopy reports lack data on segment length and biopsies have not always been taken according to the recommended Seattle protocol.4 Furthemore, information on potentially important factors was also lacking, such as gastroesophageal reflux disease, proton-pump-inhibitor consumption, obesity, smoking, dietary habits, and socio-economic factors. During most of the study period, there were no Swedish guidelines on the management of patients with BE and no explanation as to the lack of consensus regarding the follow-up time.

By contrast, some strengths of this study include the fact that the database used was large, including over 1000 patients with BE. Patients also had a long follow-up period; up to 26 years and a complete follow-up for survival. The study period was started before the routine treatment of patients with LGD was available, enabling a study of the natural course of both patients downgraded to NDBE and patients with verified LGD and IND. Although radiofrequency ablation was introduced in Sweden 2007, it was not implemented as a clinical routine therapy until 2012.21

In conclusion, the results of this study indicate that most patients diagnosed with dysplastic BE after a standard pathologist evaluation could be downgraded by a gastrointestinal expert pathologist to NDBE with a low risk of progression to cancer. Patients whose specimens were re-evaluated as IND were found to have a risk of progression to cancer in the same range as patients with confirmed LGD. This provides tangible evidence that all patients diagnoses with dysplastic BE should be re-evaluated by an expert pathologist, and suggests that patients with IND should be managed the same way as patients with LGD until better methods to distinguish true from false dysplasia are developed.

Notes

Conflicts of Interest

The authors have no potential conflicts of interest.

Funding

None.

Author Contributions

Conceptualization: PE, AT, ML; Data curation: PE, FK, ML; Formal analysis: PE, FK, ML; Investigation: PE, ÅÖ, LM, AT, BH; Methodology: PE, ML, AT; Project administration: PE, ML, AT; Resources: AT, ML, ÅÖ, LM; Supervision: ML, FK, AT; Visualization: PE, ML, AT; Writing–original draft: PE; Writing–review & editing: all authors.

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Article information Continued

Fig. 1.

Inclusion of study patients with Barrett’s esophagus.

Fig. 2.

Original diagnoses and diagnoses after a review of the biopsies from Barrett’s esophagus.

Fig. 3.

Time to cancer during follow-up of patients with Barrett’s esophagus.

Table 1.

Patient characteristics stratified by diagnosis before and after an expert pathologist review of patients with Barrett’s esophagus

Total Initial diagnosis Diagnosis after pathologists revision
HGD LGD HGD LGD IND NDBE
Total 423 8 415 3 83 71 266
Sex
 Male 304 (71.9) 5 (62.5) 298 (71.8) 3 (100.0) 65 (78.3) 51 (71.8) 185 (69.5)
 Female 119 (28.1) 3 (37.5) 117 (28.2) 0 (0) 18 (21.7) 20 (28.2) 81 (30.5)
BE length (cm) 3.7 3.4 3.7 6.7 5.0 4.8 3.0

Values are presented as number (%) unless otherwise indicated.

BE, Barrett’s esophagus; HGD, high-grade dysplasia; LGD, low-grade dysplasia; IND, indefinite for dysplasia; NDBE, non-dysplastic BE.

Table 2.

Annual incidence rate for developing cancer and incidence rate ratios in patients with Barrett’s esophagus

HGD/cancer (n) Person-years IR %/year (95% CI) IRR (95% CI) p-value
Total 34 3,872 0.87 (0.62–1.22) NA NA
Sex
 Man 28 2,784 1.01 (0.69–1.46) 1 (ref.)
 Woman 6 1,107 0.54 (0.24–1.21) 0.54 (0.18–1.33) 0.161
Age (yr)
 <50 6 768 0.78 (0.35–1.74) 1 (ref.)
 ≥50 28 3,104 0.90 (0.62–1.30) 1.15 (0.47–3.39) 0.793
Max BE length (cm)
 <3 6 1,663 0.36 (0.16–0.80) 1 (ref.)
 ≥3 27 2,209 1.26 (0.87–1.82) 3.48 (1.41–10.29) 0.002
 <10 26 3,580 0.73 (0.49–1.07) 1 (ref.)
 ≥10 7 292 2.39 (1.14–5.02) 3.30 (1.21–7.80) 0.007
Dysplasia grade
 NDBE 10 2,429 0.41 (0.22–0.77) 1 (ref.)
 IND 10 700 1.43 (0.77–2.66) 3.47 (1.30–9.29) 0.008
 LGD 14 762 1.84 (1.09–3.10) 4.46 (1.84–11.23) <0.001

IR, incidence rate; IRR, incidence rate ratio; BE, Barrett’s esophagus; HGD, high-grade dysplasia; CI, confidence interval; ref., reference; NDBE, non-dysplastic BE; IND, indefinite for dysplasia; LGD, low-grade dysplasia; NA, not applicable.