Incomplete type of intestinal metaplasia has the highest risk to progress to gastric cancer: results of the Spanish follow-up multicenter study

Introduction

Although incidence of gastric cancer (GC) is declining in many countries, it is still the fourth most common malignancy and the second leading cause of death due to cancer worldwide.1 The relative survival is very poor (only 23% at 5 years in Europe)2 and both early diagnosis and effective treatment still remain a challenge.

GC is the outcome of a very long multistep process, starting as an inflammation in the antrum, usually associated with Helicobacter pylori (H. pylori) infection, which may progress toward a multifocal chronic atrophy gastritis (CAG) in the corpus, followed by intestinal metaplasia (IM), dysplasia and finally invasive carcinoma.3, 4 It has long been recognized that IM is a heterogeneous lesion according to the histology and type of mucin secreted5 and currently they are usually sub-classified6 as “complete” (CIM) (small intestinal type) or “incomplete” (IIM) (colonic type, which is thought to be the most advanced stage of IM).

This very long multistep process represents an opportunity for early diagnosis. The identification and surveillance of patients with precursor lesions at risk of progression to GC is considered, in high or moderate risk population, as one of the most effective ways for reducing the burden of GC.7

IIM is the most advanced stage of IM and therefore has been identified as the best candidate for periodic surveillance, as well as taking into account the status of H. pylori infection and the extension of the IM.7 However, the utility of sub-typing IM as a marker of GC risk is controversial. A recently published Guideline8 recommended endoscopic surveillance for patients with extensive atrophy or IM, but did not advise subtyping IM for clinical practice, because evidence on its usefulness was considered as limited and inconsistent. In contrast, a more recent comprehensive review9 concluded that most of the scientific evidence supports the use of sub-typing IM as a predictor of GC, although recognizes that larger and better designed follow-up studies are needed to reach a definitive conclusion.

The aim of this study was to assess the progression of gastric precursor lesions, including both CIM and IIM, and to identify predictors of GC occurrence in a long term multicentric (including 9 participating hospitals) follow-up study in Spain, a population with a moderate risk of GC.1

Methods

This is an observational longitudinal study of precursor lesions of GC. During 2012 and 2013, all patients with a preliminary histological diagnoses of CAG, IM or dysplasia between 1995 and 2004, were identified from the Pathology Department's files at 9 Spanish National Health Services Hospitals in the provinces of Madrid, Barcelona, Zaragoza, Valladolid and Guipuzcoa.

A total of 1,538 patients were selected for the study, after exclusion of patients with any of the following conditions: age outside the selected 25–69 year range, peptic ulcer, Barrett's esophagus, GC or other cancer, previous gastric resection, lack of minimum quality criteria of gastric biopsy (a paraffin block including at least 3 fragments, each of one of 1.5 mm minimum size, and in which both antrum and oxintic gastric mucosa are recognized), lack of clinical or demographic information or residence outside the hospital's area.

Each patient's clinical and pathology report history was then reviewed in order to identify conditions and predefined end-points during the follow-up period from the date of recruitment (date of the validated baseline gastric biopsy) until 2012. Firstly, we identified those patients who developed a peptic ulcer or Barrett's esophagus and who were excluded as candidates for a new biopsy, because these are conditions that do not belong to the GC pathway. Secondly, we identified patients who developed a GC during the follow-up period, and those patients who had a gastric biopsy performed during the last 2 years (2010–2012). In this last situation this gastric biopsy was taken as end-point because it was considered unethical to perform a new one. Thirdly, we identified those patients who had undergone a gastrectomy for a gastric ulcer or who had died during the follow-up. In these cases, the last available gastric biopsy performed during the follow-up period was taken into account as end-point.

Patients considered suitable for a new gastric biopsy were invited by telephone call to undergo a new gastroscopy and gastric biopsy. The call was made by the same personnel performing the appointments for the gastroscopy service, following the same procedure. During the phone call the personnel explained to the patient the possible advantages of undergoing a new gastric biopsy and an appointment date was provided. During the appointment they also answered a face to face questionnaire on history of tobacco consumption, use of non-steroidal anti-inflammatory drugs (NSAID), history of diagnoses and treatment of H. pylori infection, and family history of GC. Information on these risk factors in those patients with a predefined endpoint or an event during follow-up, who could not be interviewed, was obtained by interviewing patients’ relatives, and/or from medical records. All participating patients signed an informed consent form giving permission for the procedures of the study, whose protocol was approved by the Ethical Committee of each Hospital.

Results

Out of the 1,538 patients initially identified, as potentially candidates for the study, 509 were excluded because different reasons described in the figure 1. The remaining 915 patients were invited via telephone call to participate; 587 (64%) accepted and 328 (36%) did not accept a new gastric biopsy. Therefore the analysis was based on 649 patients, including those who accepted a new gastric biopsy (n = 587) plus those with a valid end-point during follow-up (n = 62). The mean age at baseline was 52 years (SD = 10) and 54% were men.

At baseline, 156 (24%) of patients had a histological diagnosis of CAG, 248 (38%) a CIM, 219 (34%) a IIM and 26 (4%) a low grade dysplasia (Table 1). As expected, the proportion of patients classified as positive for H pylori infection was higher in less advanced lesions with a steady decrease in more advanced lesions. Prevalence of ever smokers was 52.54% and prevalence of ever use of NSAID was 46.07%, with no clear trend of consumption according to histopathological groups of diagnoses. Prevalence of family history of GC was 12.94% and this was slightly higher in patients with IM.

During a mean of 12 years of follow-up (SD = 3.4), 26 patients (4%) developed malignant tumors (Table 2). Out of them, 24 patients (3.7%) developed a gastric adenocarcinoma (21 intestinal, 2 diffuse and 1 undefined, all non-cardia GC). Two patients developed other types of tumors (1 malignant lymphoma and 1 carcinoid). Out of the 24 gastric adenocarcinomas, 15 had an incomplete IM at baseline, 8 had a complete IM and 1 had a CAG. The incidence rate of gastric adenocarcinoma was 5.76 per 1,000 person/years for those with IIM at baseline and 2.76 per 1,000 person/years for those with CIM at baseline. Overall it was 3.09 (95% CI 2.07-4.6) for 1,000 person/years.

The HR of progression to gastric adenocarcinoma was 4.17 (0.55-31.6) for those with IM at baseline, 6.42 (95% CI 0.83-49.9) for those with IIM at baseline and 2.5 (95% CI 0.3-20.5) for those with CIM at baseline, in a model using CAG as a reference category, after adjusting for sex, age, ever smoking, family history of GC and use of NSAIDs (Table 3). The HR was also high and statistically significant (2.57; 95% CI 1.06-6.26) in another model when comparing those with IIM against those with CIM at baseline. A positive but not significant association with the risk of developing a gastric adenocarcinoma was observed for those patients with a family history of GC (HR 2.10; 95% CI 0.64-6.97), and a negative but not significant association for regular use of NSAID (HR 0.84; 95% CI 0.27-2.56). Males had a higher risk of progression than females; age was not associated while ever smoking was negatively associated with risk of progression (data not shown).

Discussion

In a country with a moderate GC risk, we carried out a large observational multicentric study, with a long follow-up, in order to evaluate the occurrence of GC among patients with a baseline diagnosis of CAG, CIM, IIM or dysplasia. We found that the probability of developing a GC was higher in those with incomplete type of IM. The HR was almost 3 times higher in those with IIM than in those with CIM. None of the few patients with initial diagnosis of dysplasia developed a GC, but they were classified as low grade dysplasia, a diagnosis with low accuracy and high inter-observer variation among pathologists. On the contrary, inter-observer agreement in the classification of IM is generally considered satisfactory.12

One of every 15 patients with IIM at baseline developed a gastric adenocarcinoma during the 12-years median follow-up. Our results support subtyping IM as an useful procedure to identify subjects at higher risk for progression to GC, providing further evidence to that provided by a recent comprehensive review9 that shows that scientific evidence supports the utility of subtyping IM as a predictor of GC. In 6 of the 10 follow-up studies analyzed in this review, a statistically significant association between IIM and subsequent GC risk was found;11, 13-17 in another 218, 19 a no significant positive association was observed. These results have been observed in populations with relatively high GC risk, such as Portugal, China and Slovenia, as well as in populations with moderate GC risk such as Italy and Spain. Three of the studies that found a significant association with IIM11, 13, 16 were the largest studies and with the longest follow-up. Two of them11, 13 were the only population- based studies, which tend to be less affected by selection bias. One of these studies,16 also showed that periodic surveillance of patients with type III IM increase the probability of diagnosing dysplasia and early GC.

However, a recently published Guideline for endoscopic management of precancerous lesions in the stomach8 concluded that subtyping of IM is not recommended for clinical practice “because the evidence about its usefulness is limited and inconsistent” based on a few small studies with negative results. The other apparent limitation encountered by the authors is that “subtyping of IM requires the use of immunohistochemistry techniques that are not widespread in routine diagnostic8” which may limit its clinical application.

Nevertheless, subtyping of IM does not require the use of immunohistochemistry techniques; in fact, the classification of IM (complete or incomplete), was documented before the development of immunohistochemistry. Subtypes of IM can be easily recognized with H&E, which is the main routine histological stain widely used in clinical practice. Only in few cases the pathologists used, as additional help, the PAS-AB staining at pH 2.5, which is a standardized mucin stain.

Instead of subtyping IM, the Guideline8 advices to assess the extension of the IM. It is well known that there is a strong correlation between the type and extension of the IM. Using 12 biopsy specimens, another study20 concluded that if extensive IM is observed (in 4 or more of 12 biopsy specimens) the determination of IM subtype is not needed, because this patient should be considered as being at risk for GC, irrespective of the IM subtype. However, when only a few biopsies are available for examination (as happens in clinical practice) the finding of incomplete IM foci may be used as a surrogate to indicate that extensive metaplastic changes have been taking place and, therefore, that the patient has an increased cancer risk.

The strengths of this study are the long follow-up, the large size and the high participation rate (64%) of those patients invited for a second biopsy. On the other hand, there are also some limitations: the number of biopsies was higher at the end, when the Sidney recommendations were followed, although a minimum quality criteria of the biopsy was used to include the patients at baseline to avoid a possible bias. In clinical practice, following the Sidney recommendation is the best procedure to obtain an accurate histological diagnosis of the type of gastric cancer precursor lesions. Another potential source of error is the histological diagnoses. We were not able to assess the intra- and inter-observer agreement of the histological diagnoses in our study, because it is difficult to carry out when 9 hospitals are participating. However, we did do this in a previous study13 carried-out in a similar public hospital in another province of our country. The weighted kappa statistic was 0.58 for diagnosis of sub-type of metaplasia and 0.43 for the global histological diagnosis. For the inter-observer concordance, the ponderate kappa statistic was 0.55 for diagnosis of sub-type of metaplasia and 0.41 for the global histopathological diagnosis, what is quite acceptable, and an indicator that this potential error is not great.

In conclusion, our study indicates that sub-typing of IM is useful a method for the identification of high risk patients that require more intensive surveillance. Classification of the subtype of IM is a relatively easy, cheap and valid procedure. Gastroenterologist should request it in their routine clinical practice when a patient is diagnosed with IM. Further research is needed to investigate the role of other molecular prognostic markers of progression to GC.

Annexe. Members of the study group are

Hospital La Princesa, Madrid: Mercedes Ramas, Fernando Casals-Seoane; Hospital Universitario Rio Hortega, Valladolid: Beatriz Madrigal; Hospital Clínico San Carlos, Madrid: Francisco Sánchez-Ceballos; Hospital Universitario Príncipe de Asturias, Alcalá de Henares (Madrid): Gloria Borrego, Inmaculada Beceiro; Hospital de Viladecans, Barcelona: Merçé Barenys, Beatriz García-Zafra; Hospital de Donostia, Guipúzcoa: Angel Cosme, Mikel Larzabal; Hospital Universitario La Paz, Madrid: Jose Juan Pozo Kreilinger; Hospital Clínico Universitario Lozano Blesa, Zaragoza: Pilar Roncalés.

Conflict of interest statement

None declared

Authorship statement

Guarantor of the article: Dr. Carlos A González.

Specific author contribution:

Dr. Javier P Gisbert and Dr. José Miguel Sanz-Anquela have made a substantial contribution to research design and revising the draft.

Catalina Bonet: was in charge of the analysis of data and critically revising the draft.

JM Sanz Anquela, O. Companioni, M. Berdasco, C. López, J. Mendoza, MD Martín-Arranz, E. Rey, E. Poves, L. Espinosa, J. Barrio, Mª Á. Torres, M. Cuatrecasas, J. I. Elizalde, L. Bujanda, M. Garmendia, Á. Ferrández, G. Muñoz, V. Andreu, Mª J. Paules, S. Lario, M.J. Ramírez, Study group, J. P. Gisbert, Ramas M, Casals-Seoane F, Madrigal B, Sánchez-Ceballos F, Borrego G, Beceiro I, Barenys M, García-Zafra B, Cosme A, Larzabal M, Pozo Kreilinger JJ, Roncalés P: have collected the data, and critically reviewed the draft.

All authors approved the final version of the article, including the authorship list.