Crypt Dysplasia in Barrett’s Esophagus

from Gastroenterology Endoscopy News 2022

by McMahon Group

Crypt Dysplasia In Barrett’s Esophagus: An Update

ZOE LAWRENCE, MD SETH A. GROSS, MD

NYU Langone Health New York, New York

Endoscopic surveillance of Barrett’s esophagus can help diagnose cellular changes and prevent progression to esophageal adenocarcinoma.

Given that surveillance intervals are determined by the degree of dysplasia, an understanding of the significance of the findings is crucial.

Figure 1. Basal crypt dysplasia. The surface is mature; however, deep glands have increased mitotic activity, cribriform architecture, and luminal debris.

Image courtesy of Yvelisse Suarez, MD.

Barrett’s esophagus (BE) is defined as the presence of columnar mucosa with intestinal metaplasia of at least 1 cm within the esophagus.1 Up to 7% of patients with gastroesophageal reflux disease have histologically confirmed BE, with prevalence highest in South America, followed by North America, and lowest in Asia.2 As a precursor to esophageal adenocarcinoma (EAC), BE represents a premalignant state.3 The pathway from a healthy esophagus to cancer includes progression from erosive esophagitis to nondysplastic BE, then to lowgrade dysplasia (LGD), high-grade dysplasia (HGD), adenocarcinoma in situ, and culminates with invasive adenocarcinoma (Figures 1-3).4 As the seventh leading cause of cancer-related death among men in the United States, esophageal cancer is the subject of much research, and the early detection of changes along this dysplasia-to-carcinoma sequence can be lifesaving.5

In 2021, there were an estimated 19,260 new cases of esophageal cancer diagnosed in the United States and approximately 15,530 esophageal cancer deaths.5 Surveillance of BE can help diagnose cellular changes and prevent progression to EAC, but guidelines on endoscopic surveillance intervals are dictated by the degree of dysplasia identified.1 Thus, an understanding of the significance of the findings is required.

Under the microscope, dysplasia is characterized by architectural and cytological abnormalities. When dysplastic changes are seen in the crypt bases with preserved surface maturation, pathology will be labeled as basal crypt dysplasia or indefinite for dysplasia (IND).6,7 Significant research has gone into understanding the importance of crypt dysplasia, and we discussed the contributions to the literature on crypt dysplasia in a previous review (Gastroenterology & Endoscopy News 2019;72[7]:1-4). In this current review, we discuss advances that have been made in the past 2 years that clarify the implication of these findings.

Inflammation Versus Dysplasia

The cellular abnormalities that define crypt dysplasia can sometimes be attributed to inflammation or technical issues with specimen handling. Crush artifact and heat damage, such as the damage sustained from cautery, can lead to lack of surface epithelium or damage to the surface and inability to accurately assess the surface maturation.8,9 Similarly, crypt dysplasia or IND will often be used when there is a background of inflammation. However, unlike true dysplasia, inflammation, granulation tissue, and mucosal erosion do not cause DNA abnormality or aneuploidy. Therefore, it has been proposed that DNA content abnormality can be used for the risk stratification when IND is diagnosed. Choi et al found DNA content abnormality in 21 patients with biopsy consistent with IND, 90.5% had normal DNA, and only 1 of those patients developed HGD. The other 9.5% had abnormal DNA and developed HGD or EAC within 2 years. The research demonstrates that evaluation for DNA abnormality can differentiate true crypt dysplasia from the cellular abnormalities caused by inflammation or technical issues.8

In addition to aneuploidy alone, mutational load, or the measure of genetic aberration and instability, can be used to risk-stratify patients with IND and differentiate between those with inflammation and those with dysplasia. In a retrospective study of 28 patients with baseline IND, 88% of those who progressed to LGD or HGD had a mutational load of at least 0.5. The sensitivity and specificity for identifying patients who would progress to HGD were 100% and 85%, respectively, when using a baseline mutational load of at least 1.5. Based on this research, mutational load also can help risk-stratify patients with IND.10

More specific investigation into the cellular abnormalities that may be present in dysplasia has included assessing the presence of abnormal tumor suppressor gene p53 via immunohistochemistry among patients with BE. Redston et al found that 90% of IND patients who progressed to advanced disease had abnormal p53 compared with just 15.4% of nonprogressors.11 Patients with abnormal p53 within IND samples progressed with similar rates to patients with LGD, whereas patients with IND and normal p53 had much lower progression

Figure 2. Low-grade dysplasia. Hyperchromatic nuclei extend to the surface, with maintenance of polarity.

Image courtesy of Yvelisse Suarez, MD.

Figure 3. High-grade dysplasia. Crowded irregular glands with hyperchromatic nuclei extending to the surface, with loss of polarity.

Image courtesy of Yvelisse Suarez, MD.

rates. Since abnormal p53, like high mutational load and abnormal DNA, would not be expected to be seen in nondysplastic inflamed or damaged tissue, its presence may help differentiate between those samples with IND that are on the pathway to progression versus those that are simply inflamed.

Updates to the Literature

Most of the recent literature on crypt dysplasia in BE consists of retrospective studies. One exception is a multicenter prospective cohort study from Philips et al assessing the risk for neoplasia among patients with IND.9 They found that 24% of patients with IND developed dysplasia. In this study, length of the BE segment was the only significant risk factor for progression to neoplasia. Similarly, Shaheen et al found a correlation between BE segment length and rate of progression from crypt dysplasia to HGD or EAC.12 In this study, of 128 patients with crypt dysplasia, 3 progressed to HGD or EAC, with a progression rate of 1.42% per patient-year. Henn et al found an annual progression rate of 0.98 cases per 100 patient-years from IND to HGD or EAC among a retrospective cohort of 107 patients with IND.13 However, all cases of HGD or EAC were discovered within 1 year of initial IND diagnosis, reinforcing the need for surveillance EGD within 6 months of IND diagnosis. Among this cohort, 18.7% of patients developed LGD within a median follow-up of 2.39 years. Of note, patients with persistent IND on repeat endoscopy had a higher rate of progression, with 36% developing LGD.

One of the main challenges with understanding IND is determining whether it has a place along the metaplasia-dysplasia-carcinoma sequence. One retrospective single-center Barrett’s registry showed that the rate of progression to HGB and EAC was higher among patients with IND than among those with nondysplastic BE, and was lower in patients with IND than those with LGD.14 This pattern suggests that IND may fall along this spectrum and perhaps represents a midway point between nondysplastic BE and LGD.

To date, there is only 1 systematic review and meta-analysis evaluating the risk for progression in BE-IND. Pooling data from 8 studies with 1,441 patients, Krishnamoorthi et al found an incidence of HGD and/ or EAC of 1.5 per 100 patient-years.15 This rate is similar to the rate of progression in LGD, and the authors point out that, given the similar rate of progression as LGD, there may be a role for endoscopic therapy for IND in the future.

The American College of Gastroenterology guidelines for BE recommend that when pathology is indefinite for dysplasia, the patient should be started on twice-daily proton pump inhibitors and undergo repeat esophagogastroduodenoscopy (EGD) within 6 months.1 This recommendation has been modified from the 2015 recommendation to repeat EGD within 3 to 6 months.16 When IND is identified on the surveillance EGD within 6 months, repeat endoscopy should be performed annually.1

In comparison, patients with nondysplastic BE can wait 3 to 5 years for their next EGD, depending on the length of the segment of BE.1 This shorter interval means that patients with crypt dysplasia will have more surveillance endoscopies than those without dysplasia; although endoscopy is a safe procedure, it is not without risks, including the risks of anesthesia. Understanding of the significance of crypt dysplasia, therefore, has downstream effects on patient safety and healthcare costs.15

The American Society for Gastrointestinal Endoscopy guideline for screening and surveillance of BE does not contain specific guidance regarding interpretation or management of crypt dysplasia, but it notes that patients with crypt dysplasia may be at a higher risk for progression and points out that further research is needed to clarify the natural history of crypt dysplasia.17

Despite additional research over the past several years, the role that crypt dysplasia plays in the metaplasia-dysplasia-carcinoma sequence from BE to EAC remains ambiguous. It is clear that crypt dysplasia carries with it a risk for progression to HGD and EAC, and strides have been made toward understanding the nuances of this complex diagnosis. Further investigation and high-quality, prospective research on the significance of IND is necessary to elucidate the importance and management of this finding.

References

1. Shaheen NJ, Falk GW, Iyer PG, et al. Diagnosis and management of Barrett’s esophagus: an updated ACG guideline.

Am J Gastroenterol. 2022;117(4):559-587.

2. Eusebi LH, Cirota GG, Zagari RM, et al. Global prevalence of Barrett’s oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: a systematic review and meta-analysis. Gut. 2021;70(3):456-463.

3. Coron E, Robaszkiewicz M, Chatelain D, et al. Advanced precancerous lesions in the lower oesophageal mucosa: high-grade dysplasia and intramucosal carcinoma in Barrett’s oesophagus. Best Pract Res Clin Gastroenterol. 2013;27(2):187-204.

4. Coleman HG, Xie SH, Lagergren J. The epidemiology of esophageal adenocarcinoma. Gastroenterology. 2018;154(2):390-405.

5. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021.

CA Cancer J Clin. 2021;71(1):7-33.

6. Coco DP, Goldblum JR, Hornick JL, et al. Interobserver variability in the diagnosis of crypt dysplasia in Barrett esophagus. Am J Surg Pathol. 2011;35(1):45-54.

7. Lomo LC, Blount PL, Sanchez CA, et al. Crypt dysplasia with surface maturation: a clinical, pathologic, and molecular study of a Barrett’s esophagus cohort. Am J Surg Pathol. 2006;30(4):423-435.

8. Choi WT, Tsai JH, Rabinovitch PS, et al. Diagnosis and risk stratification of Barrett’s dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue. Gut. 2018;67(7): 1229-1238.

9. Phillips R, Januszewicz W, Pilonis ND, et al. The risk of neoplasia in patients with Barrett’s esophagus indefinite for dysplasia: a multicenter cohort study. Gastrointest Endosc. 2021;94(2):263-270.e2. 10. Trindade AJ, McKinley MJ, Alshelleh M, et al. Mutational load may predict risk of progression in patients with Barrett’s oesophagus and indefinite for dysplasia: a pilot study.

BMJ Open Gastroenterol. 2019;6(1):e000268.

11. Redston M, Noffsinger A, Kim A, et al. Abnormal TP53 predicts risk of progression in patients with Barrett’s esophagus regardless of a diagnosis of dysplasia.

Gastroenterology. 2022;162(2):468-481.

12. Shaheen NJ, Smith MS, Odze RD. Progression of Barrett’s esophagus, crypt dysplasia, and low-grade dysplasia diagnosed by wide-area transepithelial sampling with 3-dimensional computer-assisted analysis: a retrospective analysis. Gastrointest Endosc. 2022;95(3):410-418.e1.

13. Henn AJ, Song KY, Gravely AA, et al. Persistent indefinite for dysplasia in Barrett’s esophagus is a risk factor for dysplastic progression to low-grade dysplasia.

Dis Esophagus. 2020;33(9):doaa015.

14. O’Byrne LM, Witherspoon J, Verhage RJJ, et al. Barrett’s Registry Collaboration of academic centers in Ireland reveals high progression rate of low-grade dysplasia and low risk from nondysplastic Barrett’s esophagus: report of the RIBBON network. Dis Esophagus. 2020;33(10):doaa009.

15. Krishnamoorthi R, Mohan BP, Jayaraj M, et al. Risk of progression in Barrett’s esophagus indefinite for dysplasia: a systematic review and meta-analysis. Gastrointest Endosc. 2020;91(1):3-10.e3.

16. Shaheen NJ, Falk GW, Iyer PG, et al. ACG Clinical Guideline: diagnosis and management of Barrett’s esophagus.

Am J Gastroenterol. 2016;111(1):30-50; quiz 51.

17. Qumseya B, Sultan S, Bain P, et al. ASGE guideline on screening and surveillance of Barrett’s esophagus.

Gastrointest Endosc. 2019;90(3):335-359.e2.

The authors reported no relevant financial disclosures.