In a preliminary study presented at the 2002
Digestive Disease week in San Francisco, Cleveland Clinic researchers
have shown that telomerase activity is upregulated in the area of
intestinal metaplasia up to 10 years prior to development of high grade
dysplasia and adenocarcinoma by using a telomerase enzyme immunostaining
technique. Patients with Barrett’s that do not express
telomerase activity in their nuclei do not develop dysplasia.
Telomeres are DNA protein complexes essential for
the maintenance of chromosomes. They have a role in natural aging and
cancer. Normaly most human cells do not express telomerase, thus each
time a cell divides, chromosomes lose a fraction of their telomeres.
With aging telomeres eventually becomes too short to maintain chromosome
it is attached to, and the parent cell can no longer divide. In cancer
cells, however, the production of telomerase is upregulated so that the
cell division can continue indefinitely. These cell lines become
immortal and eventually kill their host.
No Dysplasia:
Presently surveillance endoscopy is recommended every two to
three years. One study showed that the interval between surveillance
endoscopy could be safely extended to five years in patients with
Barrett’s esophagus who have no dysplasia on baseline histology and
flow cytometry analysis of DNA cell content (Am J Gastroenterology 95:
1,669-76, 2000)
Low Grade Dysplasia: Guidelines from
the American College of Gastroenterology (ACG) now recommend that patients
with low-grade dysplasia undergo endoscopy every six months. If two
subsequent endoscopies are negative, since two-thirds of low grade
dysplasia is transient, annual follow up endoscopy is adequate.
High Grade Dysplasia: Progression of
high grade dysplasia to cancer may take
several years and may occur in some patients. At this time it is
difficult to predict with some degree of certainty which patients and
how many years. Furthermore to find high grade dysplasia and cancer in a
flat Barrett’s mucosa is like looking for a “needle in a hay stack”.
Mayo study of resected esophageal specimens finds that in an average of
37 cm2 Barrett’s mucosa only 1.3 cm was HGD and 1.1 cm was cancer
pointing to difficulty in finding them during surveillance and the need
for multiple biopsy samples.
My own practice is to
confirm presence of high-grade dysplasia by repeating endoscopy, obtain
more biopsy samples and make sure that at least two pathologists, one
experienced in Barrett’s and dysplasia agree with diagnosis. If
confirmed and the patient is a good surgical candidate, or if I believe
the patient will be lost in follow-up, I’ll refer the patient for
surgery and resection to centers with high volume esophagectomy.
Surgical mortality is 3-20% depending on the institution and reported
morbidity is 20-50%. However, this rate may be significantly less in
specialized centers.
Studies have shown that
close to a third of these patients have carcinomas on the resected
specimen. Loss of p53 gene on biopsy specimens also indicates a 16 folds
increase in progression to cancer compared to those who have not lost
their p53 gene. If p53 staining is available, such patients should be
strongly considered for surgery as well. In patients who are poor
surgical risks, or if they refuse surgery, then extensive medical
therapy with PPIs, NSAID and, every three months, endoscopy surveillance
is another option. Surveillance problem is sampling error and patient
compliance.
In recent years different
modalities are developed for ablation of High grade dysplasia by
applying heat, Photochemicals or mechanical resection.
Thermal techniques are:
Multipolar Electrocoagulation (MPEC), Argon Plasma Coagulation (APC),
LASERS (Nd-YAG, Argon, KTP), and Heater Probe.
Photodynamic Therapy (PDT)
using combination of porfimer sodium injection and fibers emitting
red light.
Mechanical ablation
includes: Endoscopic Mucosal Resection (EMR), and removing the area by
biopsying it.
In centers with
experienced endoscopists and endosonographers (EUS), with raised or
nodular lesions, EMR appears to be a reasonable option to esophagectomy
in patients with high grade dysplasia or adenocarcinoma limited to the
mucosal especially in patients who are poor surgical risk. It appears
logical to start the evaluation of a person with Barrett’s esophagus
with a suspicious lesion (polyp, nodule, erosion and so on) or an
already diagnosed adenocarcinoma with endoscopic ultrasound (EUS). This
can help better define the target lesion and confirm that malignancy is
limited to the mucosa. The next step would be to remove the target
lesion by EMR (strip or suck methods).
After EMR has eliminated
the area of invasive cancer, the remainder of the dysplastic mucosa can
be managed by less invasive ablative techniques like photodynamic
therapy (PDT), argon plasma coagulation (APC) or multipolar
electrocoagulation (MPEC).
It must be noted that in
one study 13% of patients with HGD who had ablation by PDT developed
carcinoma during follow up.
Chemoprevention: Aspirin and
Non-Steroidal Anti-inflammatory Drugs (NSAID) reduce relative risk for
esophageal and gastric adenocarcinomas by 40-50% through cox2
inhibition.
In Practical Terms: Roughly 20
million Americans aged 35 or older have reflux that occurs at least
weekly. 2 million of them are likely to have Barrett’s esophagus. Of
the two million, however, only 8,000 would develop adenocarcinomas. As
such, a little less than one in every 200
Barrett’s esophagus patients will develop cancer. Furthermore, most
patients with Barrett’s die of other causes (Gut, 39:5-8. 1996).
