Real-world data for endoscopic therapy in LGD: not looking so good

Abstract

Lowgrade dysplasia (LGD) in Barrett’s oesophagus (BE), due to the inconsistency in its diagnosis, identification and cancer progression, has been a management challenge for gastroenterologists. LGD, as classified by the Vienna classification, includes a histological subtype of BE where nuclei are hyperchromatic, enlarged and stratified, with this change extending to the surface epithelial cells and loss of surface maturation. However, there is a coexistent inflammationmediated epithelial injury that can make the histopathological diagnosis difficult. There is significant variability in the histopathological diagnosis and progression rates of LGD. A recent, large, multicentre study involving pathologists from the USA and Europe demonstrated that the interobserver agreement (IOA) for the diagnosis of LGD is very poor ( κ = 0.11 ). Similarly, several other studies have shown IOAs ranging from 0.17 to 0.32. 5 Similarly, there is also a wide range in progression rates (0.02%– 11.4%) from LGD to neoplasia, and other studies also report either regression or persistence of LGD without neoplastic progression. A recent study also demonstrated that BE referral centres identified high grade dysplasia/ esophageal adenocarcinoma (HGD/EAC) in 27% of the patients referred with a recent diagnosis of LGD, suggesting overestimation of neoplastic progression. Thus, the current expert best practice recommendation is to have an expert gastrointestinal pathologist confirm the diagnosis of LGD, repeat examination with whitelight endoscopy (consideration for virtual chromoendoscopy) within 3–6 months of confirmed LGD to rule out higher grade lesions, that is, coexisting highgrade dysplasia or cancer and consideration for either surveillance or endoscopic ablation (for flat lesions) as reasonable alternatives for confirmed and persistent LGD. Barrett’s endoscopic therapy (BET) is an effective treatment for LGD. The ablation of intestinal metaplasia (AIM) dysplasia trial, a multicentre randomised control trial (RCT), provided initial evidence to suggest a benefit of radiofrequency ablation (RFA) in flat, dysplastic BE (without visible lesions). Expressly, in patients with flat LGD, complete eradication (CE) of dysplasia was noted in 90.5% of the patients with RFA compared with 22.7% in controls at the end of 12 months. Similarly, a 9center Dutch RCT demonstrated 92.6% and 88.2% complete eradication of intestinal metaplasia (CE-IM) rates at 1 and 3 years among 247 patients undergoing RFA. Progression to neoplasia was seen in only 1.5% in the RFA group compared with 26.5% in the controls (absolute risk reduction (ARR) 25%). The current study by Barret et al, published in Gut, is a similar RCT comparing RFA versus surveillance for patients with BELGD conducted across 14 centres in France, trying to showcase realworld data. A total of 82 patients were randomised (RFA: 40, surveillance: 42). With a median of 3 RFA sessions (2–4), 37.5% of the patients in the RFA group achieved CEIM at 1 year that was durable at 35% at 3 years (compared with 0% in the surveillance group). 34.3% had persistent LGD at 1 year and 3 years which was significantly lower than the surveillance group (61.3% at 1 year and 58.1% at 3 years, respectively). Neoplastic progression at 3 years was lower in the RFA group (12.5%) than in the surveillance group (26.2%). However, it did not achieve statistical significance (ARR 13.7%) since it was likely underpowered for this outcome. There are several possible explanations for the low rates of BET success in this study. At first look, the data from this study alone look like RFA is mediocre for achieving or maintaining CEIM and does not impact neoplastic progression as demonstrated in the previous Dutch study. It is, however, interesting to note that only 17/40 patients were treated in highvolume centres (defined as 30 RFA/year). The CEIM/complete eradication of dysplasia (CED) rates at 3 years were significantly different between the highvolume centres (CEIM 47.1%, CED 76.5%) and lowvolume centres (CEIM 13%, CED 43.5%). Additionally, the difference in sample size, proton pump inhibitor (PPI) dosing and escape endoscopic therapy sessions might have contributed to better CEIM rates reported previously. Other factors include the use of two pathologists to confirm the diagnosis of LGD followed by a central pathology review in the Barret et al study, which led to 26% of patients downgraded from the diagnosis of LGD to non dysplastic BE (NDBE)/intedeterminate for dysplasia (IND). Finally, this was a 14community based study, and it is conceivable that previous studies could have demonstrated better outcomes on account of BET expertise centres while this represents realworld data. This study highlights the conundrum of LGD in patients with BE. In 2021, we do have to address the question of whether the diagnosis of LGD is real, or have we retrofitted a constellation of histopathological presentations into a spectrum for the ease of our understanding? If so, this might be one reason why the IOA is so poor, even for experienced GI pathologists. Finally, when experts cannot agree convincingly on the diagnosis, we are left wondering if we are treating someone incorrectly diagnosed with LGD? Is the LGD group a heterogeneous entity with some who are at a higher risk than others who behave more like the patients with NDBE? Does the diagnosis of LGD require refinement rather than persisting with this diagnosis? In our opinion, several steps need to be taken when faced with a new diagnosis of LGD. As a first step, it would be imperative to have the diagnosis confirmed by a second pathologist who has experience reviewing BE histopathology. It would also be critical to repeat a highquality white light and magnification optical chromoendoscopy and sample any suspicious areas to exclude a higherlevel lesion. Once the diagnosis of LGD is confirmed, the next step would be to elucidate the risk of progression to neoplasia based on clinical, endoscopic and histopathological findings. Following this, it would be essential to involve the patient to explain the identified risks and benefits of endoscopic treatment to facilitate shared decision making. Is there help on the way for patients with LGD? There is truly a need for making major changes in improving the risk stratification of patients with LGD either by changing the definition of this disease, using adjunct tests and biomarkers that can aid and assist today’s gastroenterologist in being able to definitively distinguish patients with LGD who would require BET. Recent studies have demonstrated Gastroenterology and Hepatology, Kansas City VA Medical Center, Kansas City, Missouri, USA University of Kansas Medical Center, Kansas City, Kansas, USA Kansas City VA Medical Center, Kansas City, Missouri, USA