Introduction

A confirmed diagnosis of low-grade dysplasia (LGD) on two endoscopies is currently considered a predictor for neoplastic progression in patients with Barrett’s esophagus (BE), and, therefore, ablation therapy is offered to these patients. However, recent studies show that aberrant expression of the p53 tumor suppressor protein might be a stronger risk factor for neoplastic progression than dysplasia status.

Aims & Methods

The aim of this study was to evaluate the value of p53 expression compared to confirmed LGD in predicting neoplastic progression in BE patients. Data was analyzed from a large prospective cohort study of 1031 BE patients (73% males, median age 61 years) with index diagnosis of non-dysplastic BE (NDBE), indefinite for dysplasia (IND), and LGD. Confirmed LGD was defined as a LGD diagnosis on 2 separate occasions, each LGD diagnosis was confirmed by two pathologists. P53 immunohistochemistry staining was performed on biopsies of 1545 endoscopies from 655 (64%) patients; both overexpression and loss of expression were considered aberrant. Neoplastic progression was defined as high-grade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Cox regression analysis was used to determine neoplastic progression risk.

Results

During a median follow-up of 8.4 (IQR 5.3-12.9) years, 68/655 (10%) patients developed HGD/EAC. Neoplastic progression was found in 20/411 (5%) NDBE patients, 25/149 (17%) patients with a single diagnosis of LGD, and 24/95 (24%) patients with confirmed LGD. P53 expression was aberrant in 28/411 (7%) NDBE patients, 50/149 (34%) single LGD patients, and 51/95 (54%) confirmed LGD patients. Aberrant p53 expression was strongly associated with an increased risk of neoplastic progression after adjusting for age, gender, segment length, esophagitis, and grade of dysplasia (HR 13.5, 95% CI 7.1-25.8). In NDBE patients, the absolute neoplastic progression risk increased from 2% with normal p53 expression to 50% with aberrant p53 expression. In patients with a single diagnosis of LGD, the progression risk increased from 6% to 35% when p53 expression was aberrant. Similar risks where found in patients with confirmed LGD, with a neoplastic progression risk of 2% with normal p53 expression and 43% with aberrant p53 expression.

Conclusion

Aberrant p53 expression is a strong predictor for neoplastic progression in BE patients. The predictive value of aberrant p53 expression is independent of the grade of dysplasia. Aberrant P53 expression may be a better parameter than (confirmed) LGD to identify patients who need close surveillance or could benefit from ablation therapy.

Introduction

During the COVID-19 pandemic the British Society of Gastroenterology (BSG) introduced interim guidelines supporting a non-biopsy pathway for the diagnosis of coeliac disease. These guidelines reflect the current recommendations of the American Gastroenterological Association (AGA). According to these guidelines, symptomatic or high risk adults with anti-Tissue transglutaminase (TTG) IgA titres ≥10× the upper limit of normal (ULN) and a positive endomysial antibody (EMA) on a repeat sample can be diagnosed without endoscopy and referred directly to a specialist coeliac clinic. Patients who do not meet these criteria should be referred for a gastroscopy (OGD) with biopsy for the confirmation of coeliac, prior to starting a gluten free diet.

Aims & Methods

To assess whether general practitioners (GPs) in the community appropriately referred patients with suspected coeliac disease in line with the AGA and BSG interim non-biopsy diagnostic criteria.
A retrospective review was conducted of all new patients referred to the Coeliac clinic in Galway university hospital between January 2023 and December 2024. Data regarding TTG level at diagnosis, EMA result, and compliance with the diagnostic pathway outlined above was collected for each new referral. This data was collected via Evolve - the hospital's electronic based patient record system.

Results

• There were 119 “new” referrals to our Coeliac Service between January 2023 and December 2024. Of these, 44 cases were known coeliac who were referred by primary care for re-engagement with the clinic, 18 were referred from secondary or tertiary care including GI surgery, Dermatology, Paediatrics, etc. 4 coincidental diagnoses (i.e. OGD performed for indications other than coeliac disease), and 5 outliers (i.e. with incomplete data or incorrectly referred to coeliac clinic) leaving 48 new coeliac cases referred from primary care.
• 18 of these referrals met the non-biopsy criteria for diagnosis (TTG ≥100 + positive EMA)
  • Within this cohort 66% (n=12) were incorrectly referred directly for an OGD which may have delayed the diagnosis of coeliac disease while the remaining 33% (n=6) were correctly referred for direct review at the coeliac clinic.
• The remaining 29 patients all had TTG values less that 10x ULN. 48% (n=14) of these patients were incorrectly referred to clinic prior to endoscopy and of greater concern, 45% (n=13) were recommended by their primary care physician to start a gluten free diet prior to any review or endoscopic procedure.
• Overall, only 44% (n=21) of referrals were compliant with the AGA/BSG guidance.

Conclusion

There is a notable gap in adherence to AGA and BSG non-biopsy coeliac diagnostic guidance in community settings. Half of patients eligible for a non-biopsy diagnosis underwent unnecessary endoscopy, and the majority of ineligible patients were commenced on a gluten free diet prior to, or without, referral for endoscopy. Further GP education is warranted to align referral practices with evidence-based pathways. Dedicated streamlined referral pathways for coeliac disease should ensure a timely diagnosis without mandatory endoscopy in those fulfilling the criteria for a non-biopsy diagnosis and facilitate a timely endoscopy prior to gluten elimination in those who require histological diagnosis.

References

Husby, S., Murray, J.A. and Katzka, D.A. (2019) ‘AGA clinical practice update on diagnosis and monitoring of celiac disease—changing utility of serology and histologic measures: Expert review’, Gastroenterology, 156(4), pp. 885–889. doi:10.1053/j.gastro.2018.12.010.
Tashtoush, L.B. et al. (2021) ‘Letter: The BSG covid‐19 interim coeliac disease guidance no‐biopsy approach is safe in adults’, Alimentary Pharmacology & Therapeutics, 54(8), pp. 1090–1092. doi:10.1111/apt.16553.

Disclosure

No conflict of interest

Clinical Case Summary

A 64-year-old woman with a prior diagnosis of type I achalasia underwent Heller myotomy with Dor fundoplication in 2015, which resulted in the resolution of dysphagia and regurgitation. However, she kept experiencing chest pain, which partially improved with nitro-glycerine. In 2018, due to worsening pain, she underwent high-resolution oesophageal manometry (HROM), which demonstrated absent peristalsis without oesophageal pressurization. Also, upper endoscopy was unremarkable, and timed barium swallow (TBS) revealed some tertiary contractions. By 2019, the patient received botulinum toxin injections with partial improvement. Another TBS performed in 2023 showed tertiary contractions in the distal third of the oesophagus, contributing to mild oesophageal emptying delay but without stasis. In 2024, repeat HROM revealed pan-oesophageal pressurization, except in the distal-most centimetres of the oesophagus. During rapid drink challenge, the patient reported pain. Given these findings, she was proposed for peroral endoscopic myotomy (POEM) to extend the myotomy proximally. In August 2024, she underwent a complete distal oesophageal myotomy, including the lower oesophageal sphincter and cardia. Endoscopic assessment in November showed no evidence of stasis, esophagitis, or resistance at the cardia. Latest clinical evaluation in March 2025 confirmed complete resolution of chest pain.
Conclusion: Non-cardiac chest pain is a less common yet challenging symptom to manage in achalasia. Its persistence after disease-directed treatment has been described in the literature, with its primary risk factor being its presence preoperatively¹. However, comparative data on different therapeutic approaches for achalasia-related chest pain remain limited. To our knowledge, only two similar cases have been reported in which pain persisted after Heller myotomy but improved following POEM, probably linked to the inadequate or incomplete myotomy of the oesophageal muscle layer^2,3.

References

1. Olvera-Prado H, et al. Predictive factors associated with the persistence of chest pain in post-laparoscopic myotomy and fundoplication in patients with achalasia. Front Med (Lausanne). 2022 Oct 14;9:941581.
2. Miftahussurur M, Tandan M, Makmun D, Nabi Z. Peroral Endoscopic Myotomy in a Patient with Achalasia Cardia with Prior Heller's Myotomy. Case Rep Gastroenterol. 2020 Jan 22;14(1):48-55.
3. Sato C, et al. Salvage therapy for postoperative residual chest pain due to esophageal achalasia. SAGES 2017 Annual Meeting in Houston [Abstract], https://www.sages.org/meetings/annual-meeting/abstracts-archive/salvage-therapy-for-postoperative-residual-chest-pain-due-to-esophageal-achalasia/