Esophageal Lining- Squamous, Glandular or Intestinal Type? A Post about GERD & Barrett Esophagus

Esophageal Surface Epithelium: Squamous, Glandular or Intestinal??

  • Normally, the esophagus is lined by simple squamous epithelium. This type of epithelium is not very good at protecting the esophagus from acid, such as the case of gastroesophageal reflux disease (GERD) where acid from the stomach seeps back into the esophagus.

  • If an acidic environment persists or there is repetitive trauma to the esophageal lining, the squamous epithelium can transform into a more protective barrier in the form of glandular epithelium. This process is called glandular metaplasia.

  • Intestinal metaplasia (aka Barrett esophagus) is the process in which goblet cells form in pre-existing nonspecific glandular metaplasia.

In theory, glandular epithelium may be seen in normal patients up to 2 cm above the GEJ. However, the true GEJ may be not be discretely identified in some patients and can be difficult to determine in the case of hiatal hernias. Thus, true measurements (2 cm cutoff) may be inaccurate.

The newer definition of Barrett esophagus requires the presence of intestinal metaplasia in the area near the GEJ as determined by the endoscopist. This means that YOU MUST SEE GOBLET CELLS ON HISTOLOGY and the endoscopist says that it was “at the GEJ”.

Another reason for the newer definition is that the presence of glandular epithelium does NOT increase the risk for adenocarcinoma, whereas seeing true goblet cells (intestinal metaplasia) has an INCREASED RISK FOR ADENOCARCINOMA. This also allows for patients that have goblet cells within 2 cm of the GEJ to be identified and properly managed.

Controversy #1: What constitutes intestinal metaplasia?

The diagnosis of intestinal metaplasia requires the presence of definitive, well-formed goblet cells These can be definitively seen on H&E stain and does not necessarily require additional stains. However, these can be helpful.
  • Commonly used stain= Alcian blue (performed at pH 2.5)- Shows strong, diffuse staining of the acidic mucopolysaccharides present in goblet cells in the surface epithelium of Barrett esophagus, but it can stain normal submucosal glands too!)

Other useful stains: Hep (HepPar 1), CDX2, Villin and MUC2 stain goblet cells, but not normal gastric epithelium. (MUC2 can stain non-goblet epithelium adjacent to or very close to goblet cells- may be an early indicator of metaplasia)

BEWARE!! Common Pitfall: Submucosal Glands

Normally, the esophagus contains a few glands in the submucosa. A few submucosal glands may resemble goblet cells and even have acidic mucopolysaccharides.

Submucosal glands are small, have a distinct lobular distribution, are arranged in tightly cohesive clusters & do NOT intermingle with the squamous epithelium.

The presence of acidic mucopolysaccharide/goblet-appearing cells in the submucosa does NOT require follow-up unless there has been intestinal metaplasia (change from squamous to glandular epithelium) .

Controversy #2: What to call glands that are not clearly goblet cells, but are not “normal” either?

  • These glands contain many features of goblet cells, but not all (often have either a partially demarcated vacuole, amphophilic cytoplasm or dispersed staining on alcian blue)

  • Some pathologists consider these glands to be early or partial intestinal metaplasia while others favor them to be a variant of normal termed “pseudogoblet cells”.

Odze and Goldblum favor the "pseudogoblet cells" to have no clinical significance. However, Not much evidence on their progression to adenocarcinoma or molecular findings are present at current time.

Recommended pathologist comment for Pseudogoblet cells:

“No definitive intestinal metaplasia seen, but cannot rule out early or partial intestinal metaplasia”

Controversy #3: How to sign out a GEJ biopsy when there are “normal endoscopic findings” but goblet cells are seen in conjunction with gastric-type epithelium?

  • Biopsies of GEJ may have intestinal metaplasia that are of gastric origin (tipoff = presence of parietal cells) as opposed to esophageal origin. Approximately 20% of “normal endoscopies” may have intestinal metaplasia in the gastric cardia.

  • Some pathologists feel any goblet cells seen (regardless of whether from esophagus or stomach) predisposes the patient for development of adenocarcinoma. Others feel seeing goblet cells in the gastric cardia (near the GEJ) may just be changes that are related to a H. pylori infection and are NOT predisposed to cancer development (thus do not need increased surveillance).

Recommended Pathologist Comment:

"Gastric-type epithelium with intestinal metaplasia of uncertain significance is present.”

Controversy #4: Do you have to see goblet cells in the pediatric population to sign it out as Barrett Esophagus?

  • Goblet cells may be rare in Barrett esophagus in children. Some pathologists feel the “old definition” of simply seeing glandular epithelium (with or without the presence of goblet cells) >2 cm above the GEJ is enough to call BE in this population.

Recommended pathologist comment:
“Glandular epithelium without definitive intestinal metaplasia is present. The clinical significance of these findings are uncertain; some degree of surveillance may be indicated if clinical suspicion remains.”

HIGH Grade dysplasia must be ruled out in any case of glandular metaplasia/Barrett Esophagus!