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Diagnostics Oncology, Technology and innovation, Biochemistry and molecular biology

A Diagnostic That’s Easy to Swallow?

At a Glance

  • The current standard of care for diagnosing Barrett’s esophagus is endoscopy, which is invasive and expensive
  • Screening, especially in high-risk patients, is key to decreasing the incidence of esophageal cancer
  • The Cytosponge, a small sponge on a string enclosed in a soluble capsule, allows sampling of the entire esophagus with a single pass
  • Combined with biomarker testing for trefoil factor 3 (TFF3), the Cytosponge may offer a new non-endoscopic solution for Barrett’s esophagus diagnosis

Much debate surrounds the question of whether or not to investigate chronic gastric reflux patients for Barrett’s esophagus. On the side of investigation, Barrett’s is a common premalignant lesion in esophageal adenocarcinoma, and early detection of the cancer can result in a survival rate up to six times higher than in later stages (1). But arguments against the testing include the invasiveness of endoscopy – currently the only widespread method of diagnosis – and the high cost. Given a way to overcome those obstacles, screening and diagnosis of Barrett’s esophagus might become an easier, more cost-effective practice that appeals to more at-risk patients. For that reason, we’ve developed just such a tool – the Cytosponge, a swallowable “sponge on a string,” paired with an objective laboratory test.

Sponge on a string

Our proposed method is a non-endoscopic diagnostic test for Barrett’s esophagus, which involves combining the Cytosponge with molecular biomarkers.

How does it work? The Cytosponge is a medical-grade polyester foam sphere on a string, compressed within a gelatin capsule that patients swallow while holding onto the string. Once swallowed, it takes about five minutes for the gelatin capsule to dissolve, allowing the foam sphere to expand to its full three-centimeter diameter. Then, using the string, the foam sphere is pulled from the stomach to the esophagus and out via the mouth, collecting cells along the entire length of its route. The sample is then put into a preservative – which allows it to be transported at room temperature and stored for up to several weeks – and sent to the laboratory for processing and testing.

Once swallowed, it takes about five minutes for the gelatin capsule to dissolve, allowing the foam sphere to expand to its full three-centimeter diameter.


The first step is to test for the presence of Barrett’s esophagus using immunohistochemistry for trefoil factor 3 (TFF3), a protein biomarker that we’ve identified as being highly specific for the condition. The TFF3 test is binary; in other words, if even a single cell stains positive for this protein, it’s indicative of Barrett’s (2). If we see a positive stain, we next test how far along the pathway to cancer the condition has progressed. We’re still in the process of perfecting the molecular analysis method, but so far, testing for mutations in the TP53 tumor suppressor gene appears to be highly specific for Barrett’s dysplasia (3).

The extent of the problem

Why is it important that a solution is found that allows the routine testing of Barrett’s esophagus? The incidence of esophageal adenocarcinoma is reported to have increased six-fold in the last two decades and carries a dismal prognosis – only 13 percent of patients survive five years. This is true despite advances in neoadjuvant therapy and surgery, and has resulted in the highlighting of this cancer as a public health concern in numerous countries. Clinical guidelines currently focus on urgent referral for those with “alarm symptoms” like weight loss and swallowing difficulties, and routine referral for those with symptoms that persist despite recommended lifestyle and pharmacological management strategies. But in patients with alarm symptoms, the cancer has often already reached an advanced stage. General practice referral rates in all instances vary widely, though, and low endoscopy referral rates have been linked with poor outcomes from esophageal cancer.

The burden of this cancer should be as much as halved by increasing the proportion of individuals with reflux-predominant symptoms who are investigated.


Three to six percent of individuals with reflux-predominant symptoms may have Barrett’s esophagus, the precursor lesion to esophageal adenocarcinoma, but less than a quarter of patients with Barrett’s are diagnosed. It’s estimated from some modeling studies (4) that the burden of this cancer could be as much as halved by increasing the proportion of individuals with reflux-predominant symptoms who are investigated. But that’s no easy task, since dyspepsia and gastroesophageal reflux symptoms affect between five and 20 percent of the population and account for up to one-tenth of all GP consultations in the UK alone – and with recent national awareness campaigns, that number will only increase. Given the scale of the problem, and the cost of investigation, any new strategy needs to be carefully evaluated. To that end, Liam Donaldson, former Chief Medical Officer for England, highlighted the problem of esophageal cancer in his 2007 annual report (5) and recommended researching “new diagnostic techniques, including potential minimally invasive screening tests.”

Endoscopic treatment of Barrett’s, which progresses through dysplastic and superficially invasive stages, offers the opportunity to prevent the development of esophageal adenocarcinoma. Indeed, endoscopic treatment is now recommended by the UK National Institute for Health and Care Excellence and most international gastroenterology societies for patients with low- and high-grade dysplasia, following new evidence from randomized controlled trials. That’s why we decided to develop an alternative test for Barrett’s that would be suitable for primary care, acceptable to patients, and provide an accurate diagnosis at an affordable price to enable widespread use. At the same time, we’ve been very keen to develop molecular tests that not only diagnose Barrett’s, but also risk-stratify patients, so that we can design better surveillance practices that work for patients and clinical services.

Challenges in the clinic

For me, the biggest challenge is also the greatest reward – getting to work across a range of disciplines including manufacturing, public health, primary care, health economics, biomarkers and trial design. It’s surprising how long it takes for an idea to be adopted into clinical practice. We’ve been working on the Cytosponge for over 10 years, and even though we’re making progress now, we still have a long way to go.

In a series of four clinical studies, we’ve demonstrated the effectiveness of the Cytosponge.

In a series of four clinical studies, we’ve demonstrated the effectiveness of the Cytosponge. A feasibility study conducted in 504 patients over 11 general practices showed that it can successfully be applied to primary care, and that it’s transferable to the UK National Health Service (NHS) – 27 nurses were taught to use it in a single training session, with sample processing done in an NHS pathology laboratory. It’s also cost-effective compared with the current standard of care; a microsimulation model suggested a gain of 0.015 QALYs (quality of life years) and an ICER (incremental cost-effectiveness ratio) of $15,700 per QALY for Cytosponge versus endoscopic diagnosis of Barrett’s esophagus followed by endoscopic treatment. It’s even acceptable to patients, scoring a mean of 6 on a visual analog scale of satisfaction from 0 to 10. And as well as being practical and popular, it’s had good results so far too – 2,000 patients who have been screened using the Cytosponge have shown no serious adverse events related to the device, and the test has accurately diagnosed Barrett’s esophagus regardless of patient cohort or study setting (see Table 1).


Table 1: Sensitivity and specificity of the Cytosponge-TFF3 test throughout the course of four studies.
Study Published Type Setting Barrett’s length Sensitivity % (95% CI) Specificity % (95% CI)
Pilot (6) 2007 Cohort Secondary care ≥C1 78.0 (64.0–89.0) 94.0 (87.0–98.0)
BEST1 (7) 2010 Prospective Primary care ≥C1 73.3 (44.9–92.2) 93.8 (91.3–95.8)
        ≥C2 90.0 (55.5–99.7) 93.5 (90.9–95.5)
BEST2 (2) 2015 Case:control Secondary care ≥C1 79.5 (75.9–82.9)  
        ≥C2 83.9 (80.0–87.3) 92.4 (89.5–94.7)
        ≥C3 87.2 (83.0–90.6)  
CASE1 (8) 2015 Cohort Secondary care ≥C1 or ≥M3 95.4 (86.9–98.9)  
        ≥C3 96.8 (83.7–99.5) N/A
Practical pathology

Unlike the multiple biopsies collected in endoscopy, the Cytosponge collects only a single sample. But owing to the nature of its collection, there is minimal sampling bias; in an experiment to investigate the clonal architecture of Barrett’s esophagus, we demonstrated that in a patient with six separate clonal areas of dysplasia, all six were sampled on a single Cytosponge test (2). At the moment, the collected sample is processed to a paraffin block and sectioned for TFF3 immunohistochemistry. For risk stratification, the remaining block is then processed for DNA extraction and TP53 mutation analysis, but the optimal method of stratification is still part of our ongoing research.

Our ultimate goal is to increase the number of individuals in primary care who are tested for Barrett’s esophagus without adding to the burden on endoscopy departments. The samples will still need to be processed, but we’re expecting that to be part of the commercial kit so that the results can go straight to the clinician requesting the test. For patients with known Barrett’s esophagus, this could be a much more efficient test than multiple biopsies, and lead to a more objective readout than the current diagnosis of dysplasia. But in the longer term, it could be rolled out as a screening service as well, if it continues to be cost-effective and meets the World Health Organization screening criteria.

As a priority we’d like to see the Cytosponge-TFF3 technology adopted as a triage test within the standard primary care clinical pathway for patients with reflux-predominant symptoms. That strategy would increase the proportion of patients diagnosed with Barrett’s esophagus. In addition, we hope that it will replace the current endoscopic surveillance protocols, which are invasive, expensive, limited by sampling bias, and result in a subjective readout. A Cytosponge-sampled, biomarker-based surveillance test has the potential to address all of those limitations, so that we can effectively identify the patients at greatest risk of esophageal adenocarcinoma.

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  1. P Sharma, EI Sidorenko, “Are screening and surveillance for Barrett’s esophagus really worthwhile?”, Gut, 54, i27–i32 (2005). PMID: 15711005.
  2. CS Ross-Innes, et al., “Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett’s esophagus: a multi-center case-control study”, PLoS Med, 12, e1001780 (2015). PMID: 25634542.
  3. JM Weaver, et al., “Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis”, Nat Genet, 46, 837–843 (2014).PMID: 24952744.
  4. TL Vaughan, RC Fitzgerald, “Precision prevention of oesophageal adenocarcinoma”, Nat Rev Gastroenterol Hepatol, 12, 243–248 (2015). PMID: 25666644.
  5. Department of Health, “2007 Report of The Chief Medical Officer” (2008). Available at: Accessed September 3, 2015.
  6. P Lao-Sirieix, et al., “Non-endoscopic immunocytological screening test for Barrett’s esophagus”, Gut, 56, 1033–1034 (2007). PMID: 17566045.
  7. SR Kadri, et al., “Acceptability and accuracy of a non-endoscopic screening test for Barrett’s oesophagus in primary care: cohort study”, BMJ, 341, C4372 (2010). PMID: 20833740.
  8. P Lao-Sirieix, et al., “Evaluation of a minimally-invasive cytosponge esophageal cell collection system in patients with Barrett’s esophagus”, Gastroenterology, 148, S-16 (2015).
About the Author
Rebecca Fitzgerald

Rebecca Fitzgerald is a Medical Research Council program leader at the MRC Cancer Unit and an honorary consultant in gastroenterology and general medicine at Addenbrooke’s Hospital, Cambridge, UK. She also holds a personal chair in cancer prevention at the University of Cambridge.

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