Esophageal adenocarcinoma (EAC) is a disease with a poor prognosis at advanced stages.
Identifying esophageal adenocarcinoma at an early stage allows for endoscopic treatment to
reduce mortality and morbidity for these treated patients. Adequate surveillance strategies
with appropriate risk stratification are therefore essential. The current endoscopic
surveillance protocol relies on systemic four-quadrant biopsy at 2-cm intervals of the BE
segment, with additional targeted biopsies from visible abnormalities.
Obtaining random biopsies is time consuming, and it results at best in sampling less than 5%
of the BE surface area . Thus, significant sampling error is inevitable. Sampling the BE
segment with a brush has the theoretical advantage of larger field sampling and might
therefore increase the detection of dysplasia. Conventional brush cytology samples however,
suffer from superficial sampling and difficult analysis of the thick tissue smear by a
twodimensional cytology microscope. The WATS system (developed by CDx Diagnostics) consists
of a trans-epithelial cytology brush designed to sample cells from all three layers of the
epithelium and the diagnosis of the brush specimen by advanced computer image analysis system
at CDx Diagnostics.
These advantages over conventional cytology may make this system an important diagnostic tool
in BE surveillance . In the European WATS study ("Euro-WATS1") the WATS-system was compared
with random biopsies in a cohort of patients referred with low-grade dysplasia (LGD),
high-grade dysplasia (HGD) or early cancer after removal of all visible abnormalities.
Eligible cases underwent random biopsies and WATS brushings after randomizing the order of
sampling.
The study showed no significant differences in the detection rate for HGD or EAC between
random biopsies and WATS brushings. The brush detected 39/48 HGD/EAC cases versus 30/48 for
random biopsies (p=0.12). The value of the WATS-3D brush as an adjunct to random forceps
biopsies however, was 48/147 vs 30/147; difference 12%, with a number needed to treat of 8.
Moreover, the brush had a significantly shorter procedure time than random biopsies with a
larger difference in longer BE segments. Another strength of the WATS brush, compared to
random biopsies, is that it paves the way towards a preferred (future) trans-oral sampling
instead of endoscopic sampling. Key element in the adjunctive value of WATS is the clinical
relevance of "WATS-positive-biopsy-negative". One may argue that the morphological changes of
dysplasia-positive WATS samples clearly correspond to those defining dysplasia in biopsy
samples and therefore are merely different representations of the same disease which is now
diagnosed at an earlier stage. Others argue that the WATS-system, by being more sensitive to
detect dysplasia, simply dilutes the disease reservoir with clinically less severe cases
which do not warrant the same therapeutic approach as in cases with a biopsy based diagnosis
of dysplasia. The natural history of "WATS-positive-biopsy-negative" cases can, however, not
be investigated in the EUROWATS1 study because this was a transversal study with no
subsequent follow-up and with the vast majority of cases having undergone ablation therapy
based on their referral diagnosis and/or outcome of the endoscopic resection of visible
lesions. Another limitation of the EURO-WATS1 study was the relatively high rate of WATS
brushings that were deemed ineligible for assessment of the smears. In the study 23/172 (13%)
of cases had suboptimal WATS samples, despite the fact that the corresponding cellblocks
showed adequate cellularity. It appears that the logistics in the endoscopy suite and/or
storage of samples prior to transportation and evaluation at CDx may have had flaws.
Therefore, a second European WATS study ("WATS EURO 2 study") will be performed in which,
after the baseline endoscopy with WATS brushing and random biopsies, endoscopic follow-up is
continued until a biopsy-based diagnosis of HGD or cancer is made. The WATS EURO 2 study will
therefore allow us to study the natural history of WATS-positive-biopsynegative cases, will
enable us to re-evaluate the role of the WATS-3D brush as a potential substitute for random
sampling, after optimizing sample collection and preparation in the study. Finally, the
samples collected in this study will also allow us to perform future biomarker studies on
both the brush and biopsy material, to find the best sampling method for biomarker risk
stratification in the future. It is undisputed that patients referred with LGD, HGD or early
cancer should have all visible lesions removed by ER techniques. In general, the endoscopic
resection specimen will then show a diagnosis of HGD or early cancer. Follow-up studies have
shown that the chance of the development of metachronous HGD/EAC in the remaining BE segment
is about 10% per year. Therefore ablation therapy is advised for the remaining BE segment.
The same 10% annual progression rate to HGD/EAC applies for patients with a confirmed
diagnosis of LGD. For these patients, guidelines suggest that ablation therapy may be a valid
alternative to subsequent surveillance. The actual decision to ablate the remaining Barrett's
segment after endoscopic resection of HGD/EAC or to prophylactically ablate for LGD, is made
on a per patient basis in which age and comorbidity are important additional factors to be
taken into account. Follow-up studies after ER of visible lesions containing HGD/EAC have
found that metachronous lesions are all found at an endoscopically treatable stage with the
majority of patients not developing recurrent disease. The same holds for prophylactic
ablation in cases with LGD: a significant proportion of patients will not progress or not
even manifest their baseline diagnosis of LGD upon follow-up. In the SURF-study, 30% of the
LGD-patients randomized to endoscopic surveillance did not have their LGD diagnosis
reproduced during 4 subsequent endoscopies in 3-years follow-up and all cases that progressed
to HGD/EAC were diagnosed at an endoscopically curable stage. Furthermore, RFA still is
accompanied by complications such as esophageal stenosis and requires multiple hospital
visits. Even upon complete endoscopic eradication of all Barrett's mucosa, guidelines still
dictate endoscopic surveillance after ablation virtually at the same frequency as for
Barrett's cases not prophylactically treated. Therefore, keeping Barrett's patients under
strict endoscopic surveillance after ER of visible lesions or for flat LGD is an acceptable
strategy that does not divert from current guidelines.
In the current study, the investigators aim to study the rate of developing a biopsy-based
diagnosis of HGD/EAC in Barrett's patients at high risk of progression (i.e. after endoscopic
removal of visible lesions containing HGD/EAC and/or a diagnosis of LGD) as well as in
patients in a standard Barrett's surveillance program. In these patients the investigators
will combine biopsy sampling with WATS brushing at baseline and all follow-up endoscopies.
This will allow us to study the natural history of WATS-positive-biopsy negative case and of
WATS-specific outcomes such as basal-crypt dysplasia, and to further evaluate the role of the
WATS brush as a potential substitute to random biopsies.
The study also allows us to collect specimens for future biomarker studies that may help to
predict progression to HGD/EAC in the absence of morphological features of dysplasia.