Footnotes

Some extra notes, discussions and observations by the author.

Definition of Barrett's Oesophagus

When he discovered the condition that now carries his name, Norman Barrett described what he saw as a short oesophagus with an elongated stomach.

The cells in the oesophagus are supposed to be squamous which lie like flat plates or, as described in the chapter on Barrett's, like dominoes lying flat.

Stomach cells, on the other hand, are columnar in nature - like the dominoes standing on end.

Norman Barrett was a thoracic surgeon rather than a gastroenterologist. His observation of columnar cells further down the oesophagus than squamous cells, led to his erroneous conclusion. Two other surgeons, Philip Allison and Alan Johnstone identified the area as actually still the oesophagus but bearing cells that were alien to this organ, calling them "Barrett's Ulcers".

In 1957, the condition was referred to as columnar lined oesophagus, or Columnar Epithelium Lined Lower Oesophagus (CELLO) but this was gradually replaced by the term Barrett's Oesophagus.

In UK, Barrett's is still defined as columnar cells in the lower oesophagus.

There are, however, two forms the columnar cells can take: "Cardial Metaplasia" (resembling the cells normally lining the stomach) or "Intestinal Metaplasia" (resembling the cells normally lining the intestines). Essentially the difference is the existence of "goblet cells" which are small extra cells found amongst some of the columnar ones. To expand the domino metaphor, they may be pictured as putting an occasional grape at random between some of the upstanding dominoes.

The UK definition remains unchanged. If goblet cells are a prerequisite to the mutation of Barrett's to cancer, if they're not found in biopsies, it could be argued that, due to their paucity, they may have been missed.

The US definition, however, specifies the goblet cells must be present. That means Intestinal Metaplasia is considered Barrett's in US, whilst Cardial Metaplasia is not. The reason is, due to the location of Barrett's cells being at the z-line (junction of oesophagus and stomach), biopsies may accidentally be taken below the line harvesting perfectly normal cardial cells which may be incorrectly identified as Barrett's.

Goblet Cells

The role of goblet cells in the mutation to adenocarcinoma isn't without contention.

This November 2012 article in Clinical Gastroenterology and Hepatology: Barrett’s Esophagus: Is the Goblet Half-Empty? quotes from the American Gastroenterological Association medical position statement on the management of Barrett's esophagus:

The authors ... wrote that, “Presently, intestinal metaplasia [with goblet cells] is required for the diagnosis of Barrett’s esophagus because intestinal metaplasia is the only type of esophageal columnar epithelium that clearly predisposes to malignancy.” That statement remains valid. Although there are contradictory data, most evidence suggests that non-goblet columnar cell epithelium in the esophagus is not strongly predisposed to malignancy.

However, this paper published in Gut in 2015: Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus concluded, "Our data demonstrate the premalignant potential of metaplastic columnar epithelium without goblet cells in the context of Barrett's oesophagus."

To add to the confusion, this paper published in PLoS One in 2015: High Goblet Cell Count Is Inversely Associated with Ploidy Abnormalities and Risk of Adenocarcinoma in Barrett’s Esophagus suggested "Goblet cells may represent a potentially successful adaptive response to acid and bile by producing a thick mucous barrier that protects against cancer development in Barrett's esophagus (BE). The aim of this study was to determine the relationship between goblet cells (GC) and risk of progression to adenocarcinoma, and DNA content flow cytometric abnormalities, in BE patients." and concluded, "The results of this study show, for the first time, an inverse relationship between high GC counts and flow cytometric abnormalities and risk of adenocarcinoma in BE. Further studies are needed to determine if GC depleted foci within esophageal columnar mucosa are more prone to neoplastic progression or whether loss of GC occurs secondary to underlying genetic abnormalities."

With detection of goblet cells key to cytology identification of Barrett's and adenocarcinoma, the debate continues.

This paper, Barrett’s Esophagus and Intestinal Metaplasia, published in Frontiers in Oncology 17 June 2021, discusses the significance of IM for development of Barrett's.

"Replacement of the distal esophageal squamous epithelium by metaplastic columnar epithelium forms the pathological basis for BE. Whether IM must be present or whether the length of the columnar mucosa needs to be larger than 1 cm are the main controversial points. The American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), and European Society of Gastrointestinal Endoscopy (ESGE) all believe that IM is necessary for the diagnosis of BE, while the British Society of Gastroenterology (BSG), Asia-Pacific Working Group (APWG) and Benign Barrett’s and Cancer Taskforce consensus group (BOB CAT) all reckon that IM is not needed for the diagnosis of BE. However, BOB CAT also stressed that the existence of IM should be noted when diagnosing BE"  

This 2023 paper "Understanding the malignant potential of gastric metaplasia of the oesophagus and its relevance to Barrett’s oesophagus surveillance" found "GM does not bear the mutational hallmarks of OAC, with an absence of associated signatures and driver gene mutations. Finally, we established that GM found adjacent to OAC is evolutionarily distant from cancer." supporting the suggestion of patients with GM not warranting inclusion in a surveillance program for Barrett's oesophagus. However, Dr Stuart Jon Spechler commenting in Practice Update commented, "although GM might lack the mutational hallmarks of adenocarcinoma, it conceivably might develop those hallmarks if it transforms into IM. Indeed, a recent clonal analysis study has suggested that the cardiac-type gland is the likely common ancestor of all the Barrett’s phenotypes." (See Research Finds BE Is Caused By Stomach–Intestinal Cell Hybrid)

Calculating the risk of dying if Barrett's becoming cancerous

If we know the number of people with Barrett's (n), and the number of people dying from oesophageal adenocarcinoma (m), the risk factor can be obtained by simple mathematics: n/m*100 %

Determining the number of people in a population who have Barrett's, has difficulties. See this discussion paper provided for Barrett's Wessex for their "Burning Questions" series, relating  to UK statistics: How Common is Barrett's?

Applying the Mayo Clinic guidance of one in 20 of a population having Barrett's to the UK population of around 64 million provides for 3.2 million with the condition. Using Cancer Research UK statistic of around 8,000 deaths to oesophageal adenocarcinoma annually provides a annual risk factor in UK of about 0.25% or one in 400.

Using the same criteria applied to US statistics, provides an annual risk factor for Barrett's mutating to adenocarcinoma death in America at about 0.1% or one in 1000

These figures informed the graphical representation for the World Barrett's Day website, shown below.

Lifetime risk of Barrett's leading to death from oesophageal adenocarcinoma is much less easy to establish with various studies by Barrett's registries suggesting 1 in 10 or 1 in 20. Observation following over 10,000 with Barrett's Esophagus on a Facebook forum appears to have only revealed 3 deaths in 9 years, whereas using US risk factors described above may expect 10 a year, but those patients know they have Barrett's and are taking medication and receiving regular surveillance.

Reduced risk amongst those who know they have Barrett's

In the Facebook group, BarrettsEsophagusAwareness, there are in 2024 over 12,000 members.

Ten years ago, in 2014, there were 2,000 members.

The median is around 7,000 members.

If 70% have Barrett’s & follow rules, that gives about 5000 members with about 50,000 patient years.

In 10 years, there have only been 3 deaths to the cancer.

That provides a risk ratio of about 0.006% - or virtually zero.

Page updated 14 February 2024