Why is gastric cancer often diagnosed too late?

Professor Tamara Matysiak-Budnik – Professor of Gastroenterology and Digestive Oncology at the Institute of Digestive Diseases (IMAD), Nantes University Hospital, France

Gastric cancer is responsible for over 4,000 deaths in the UK every year, approximately 54 % of which would have been completely preventable¹ with earlier detection and prompt intervention. Despite this, very little progress has been made to improve the diagnosis of the disease in the last 30 years, and patients are often investigated only at a later, less treatable stage. In this series of blogs, Professor Tamara Matysiak-Budnik – Professor of Gastroenterology and Digestive Oncology at the Institute of Digestive Diseases (IMAD), Nantes University Hospital – discusses why gastric cancer is typically diagnosed later than other cancers, and how the situation can be improved with a multi-step screening approach that relies on endoscopy and serological tests.

A deadly diagnosis

Gastric cancer is the fifth most common cancer, resulting in the third most cancer-related deaths worldwide.² While the incidence is relatively low for most of Europe compared to Asian countries – with a few notable exceptions such as Portugal and some Eastern European countries,^2,3 – it is often diagnosed at a later, less treatable stage with a disappointing 30 % five-year survival rate,⁴ making it one of the most deadly cancers. There are a number of contributory factors, but the major ones are the late diagnosis and a general lack of awareness with regards to preventative actions.

Inconsistency in disease diagnosis

There are two types of gastric cancer based on localisation: one that develops in the upper stomach known as the cardia, and one that develops lower down in the non-cardia region. These conditions differ in more than just topographical sites; they also have different risk factors, carcinogenesis and epidemiological patterns, which can complicate the diagnosis and prevention of gastric cancer as a whole.² Most non-cardia gastric cancers, particularly adenocarcinomas, develop as a result of a cascade of phenotypic alterations – gastric atrophy (GA), gastric intestinal metaplasia (GIM) and gastric dysplasia – most often initiated by a chronic Helicobacter pylori infection. These so-called premalignant lesions provide a window of opportunity to both identify gastric cancer risk and put in place preventative measures, such as H. pylori eradication and proper surveillance.² However, in practice, there are gaps and inconsistencies in the diagnostic pathway.

Are treatments doing more harm than good?

The opportunity for early diagnosis is frequently overlooked by the fact that empirical treatment is often prescribed to patients with GI complaints without any diagnostic tests or investigations, typically using proton pump inhibitors (PPIs) to reduce gastric acidity. This is far from ideal as PPIs simply cover up symptoms, running the risk that early precancerous lesions may be missed. In addition, recent studies have also suggested that the overuse of PPIs may potentially contribute to the development of cancer through the elevation of gastrin levels and modification of gastric and intestinal microbiota, although these findings require further confirmation.⁵

Relying on a subjective lens

When patients have persistent symptoms, they can be referred for further investigation and surveillance, usually by endoscopy, which is an invasive procedure and sometimes not easily available. There is currently no universally-used pathway for determining patients at high risk of gastric cancer that may require endoscopic investigations and further surveillance, leaving some patients to be identified too late, and other non-risk patients to be investigated unnecessarily. Furthermore, a subset of patients with gastric precancerous lesions do not have any symptoms at all, which makes it even more difficult to identify these at-risk patients.

Once high-risk patients have been identified, the process of surveillance is not completely established. Several national and international bodies have tried to address discrepancies in surveillance for patients with known precancerous lesions by establishing guidelines that detail when and how to manage gastric changes. For example, the European Management of Precancerous Conditions and Lesions in the Stomach (MAPS II) recommends that individuals with advanced stages of atrophic gastritis or intestinal metaplasia should be followed up with endoscopic surveillance every three years, and the British Society of Gastroenterology recommends the same for patients with extensive GA or GIM.^6,7 However, it is not always clear how to adapt the modalities of surveillance to each patient depending on their individual risk.

In principle, these guidelines are an important step in the right direction, but there is growing concern surrounding the reliance on endoscopic biopsies for investigating the state of the gastric mucosa, as the reliability of the method rests heavily on the quality of the examinations. Endoscopy alone is adequate for identifying big, macroscopically visible lesions, however precancerous lesions are usually not visible with standard endoscopic techniques, making biopsies necessary. New endoscopic techniques – such as virtual chromoendoscopy with magnification – offer much better visualisation of lesions, but still, according to the MAPS guidelines, the biopsies are necessary for histopathological analysis allowing the precise evaluation of the severity of the lesions. However, these evaluations are always at risk of introducing sampling errors due to the often patchy distribution of gastric lesions on the mucosa; the tissue that is biopsied represents only a tiny percentage of the large surface of the gastric mucosa, and the choice of the sample site can have a significant impact on the results.

There have been several attempts to improve the consistency of this subjective method, including the implementation of the Updated Sidney System (USS), which recommends taking biopsies from the antrum, incisura, lesser curve and greater curve of the stomach.⁸ However, this protocol is not always followed and it still only examines a very small cross section of the entire mucosa, leading to potentially undiagnosed cases. According to the European Society of Gastrointestinal Endoscopy, a thorough investigation requires endoscopists to spend at least seven minutes on each examination.⁹ However, in practice, the procedure has to be shortened to prevent prolonging patients’ discomfort. Endoscopy is invasive and uncomfortable, and many patients are apprehensive – particularly as pain relief is not always available – but rushing can leave room for error.

What’s next?

Clearly, endoscopy may be insufficient to identify precancerous lesions that are not always visible, and biopsies are always subject to sampling errors as lesions can be dispersed in the mucosa. Therefore, a more objective, global test that is able to reflect the state of the entire gastric mucosa is very important, even as a complementary diagnostic tool to endoscopic biopsies. Non-invasive tests for stomach-specific biomarkers – such as Pepsinogen I, Pepsinogen II and Gastrin 17 – can do this by providing more clarity about the function of the gastric mucosa and, with that, pinpointing the location of possible lesions. However, there is still some debate as to when it is the most effective time to implement serological testing. Screening programmes for certain patient demographics – according to age and risk groups – have been used to good effect in Asian territories and globally for other significant conditions, and this would almost certainly be a step in the right direction for gastric cancer too.

Read the next blog in this series to discover how structuring a national screening programme has successfully reduced mortality from gastric cancer in high incidence countries.

To find out more, visit www.biohithealthcare.co.uk/biohit-product/gastropanel-pepsinogen-i-pepsinogen-ii-h-pylori-igg-and-gastrin-17-elisas

References

1. Cancer Research UK. Stomach cancer statistics. Accessed 2^nd May 2023. https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/stomach-cancer.
2. Matysiak-Budnik, T. From premalignant lesions to early gastric cancer risk. Accessed 22^nd May 2023. https://www.imad-nantes.org/images/IMAD/pdf/CG-ebook-FINAL-Version-2_compressed.pdf
3. Morais, S., et al. Trends in gastric cancer mortality and in the prevalence of Helicobacter pylori infection in Portugal. European journal of cancer prevention, 25(4), 275-281. (2016).
4. Anderson, L. A., et al. Survival for oesophageal, stomach and small intestine cancers in Europe 1999–2007: results from EUROCARE-5. European Journal of Cancer, 51(15), 2144-2157 (2015).
5. Huber, M. A. et al. Does Chronic Use of High Dose Proton Pump Inhibitors Increase Risk for Pancreatic Cancer? Pancreas, 51, 1118–1127. (2022).
6. Pimentel-Nunes, P. et al. Management of epithelial precancerous conditions and lesions in the stomach (MAPS II): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), European Society of Pathology (ESP), and Sociedade Portuguesa de Endoscopia Digestiva (SPED) guideline update 2019. Endoscopy, 51, 365–388 (2019).
7. Banks, M., et al. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut, 68(9), 1545-1575. (2019).
8. Stolte, M., & Meining, A. The updated Sydney system: classification and grading of gastritis as the basis of diagnosis and treatment. Canadian journal of gastroenterology, 15(9), 591-598. (2001).
9. Bisschops, R., et al. Performance measures for upper gastrointestinal endoscopy: A European Society of Gastrointestinal Endoscopy quality improvement initiative. United European Gastroenterology Journal, 4(5), 629-656. (2016).