Background: Incomplete intestinal metaplasia (IM) is reportedly associated with higher gastric cancer (GC) risk than its complete variant. AGA Guidelines recommend including IM subtyping in routine pathology reports. This study assesses the prevalence of complete versus incomplete IM in gastric conditions with different GC risks. Methods: IM subtyping (complete vs. incomplete) and grading (IM extension: G1: ≤30%; G2: >30%) were assessed in 386 patients with IM + ve gastric biopsy sets that included both antral and oxyntic samples. Cases were categorized as: (a) IM foci in otherwise normal mucosa (n = 59); (b) Helicobacter pylori gastritis (n = 138); (c) reactive gastropathy (141); and (d) autoimmune atrophic gastritis (AIG, n = 48). Odds ratios (OR) and their 95% CI were used in comparing the prevalence of incomplete IM and the correlation between subtype and IM extension. Results: Incomplete IM was present in 37.7% of patients with H. pylori gastritis, 8.3% of those with AIG 5.0% of those with reactive gastropathy, and none of those with otherwise normal mucosa. Incomplete IM was strongly associated with more extensive (G2-IM) mucosal intestinalization (OR = 6.69; 95% CI = 2.77–9.40). Conclusion: Incomplete IM is significantly more prevalent in conditions (H. pylori gastritis) known to carry a higher risk of GC and is strongly associated with its extension. The low prevalence of incomplete IM in AIG (8.3%) and reactive gastropathy (5.2%) is in keeping with the low GC risk associated with these conditions.

Intestinal metaplasia (IM), a component of the spectrum of gastric mucosal atrophy, has been suspected to be a precursor of gastric cancer (GC) and included among early gastric precancerous lesions since the XIX century [1]. Morphologic, histochemical, and immunophenotypic studies as well as molecular profiles have subsequently distinguished different IM subtypes, putatively associated with different cancer risk [2].

Complete-type IM (also referred to as small intestinal type, or type I) mimics the normal mucosa of the small intestine, with orderly arranged absorptive cells with a polarized brush border, mostly secreting low-acid sialomucins, and with intermingled Paneth cells. The incomplete type (colonic type, or type III) shows loosely arranged mucosecreting cells with no brush border, sulfated mucins (MUCs) in both goblet and columnar cells, and the absence of Paneth cells [3, 4]. A third IM variant (incomplete, type II IM) shows an intermediate MUC pattern, recognizable only by combining qualitative MUC histochemistry with their intracellular location [5]. Even when histochemistry is used, however, IM subtyping based on the histochemical expression of MUCs requires considerable operator experience, and its clinical reliability is conditioned by the consistency of the biopsy sampling protocol. MUC immunohistochemistry can also be used to classify the different IM subtypes; while all IM subtypes express MUC2 and MUC4, the expression of MUC5AC and MUC6 are decreased in the complete variant [6‒8]. Again, the use of these sophisticated cytochemical and immunohistochemical distinctions is restricted to the research setting. Routine diagnostic practice dichotomizes IM in the two “cardinal” variants, namely, complete versus incomplete.

In a significant proportion of cases, different subtypes of IM coexist; in such cases, due to the higher cancer risk associated with the incomplete variant, metaplasia is best categorized as incomplete [9, 10]. Based on this simplified distinction, the clinical impact of IM has been recently addressed by a focused conference sponsored by the American Gastroenterological Association (AGA) [11], and management guidelines have been issued by other national and international gastroenterological organizations [12] as well as expert committees [13] and individual specialists [5]. The AGA has recently issued guidelines for the management and follow-up of patients with IM [6‒8].

Well-established evidence associates the colonic-type variant with a higher risk of GC. Several studies have documented a significant relationship between the extent of IM and its type, showing that the greater the extent of gastric intestinalization, the greater the proportion of incomplete IM, and the higher the risk for GC. Therefore, it has been recommended that pathology reports include the type (sometimes also referred to as “subtype”) of IM.

Long-standing Helicobacter pylori infection is the major cause of atrophic gastritis, characterized by multiple foci of atrophy and IM involving both antral and oxyntic mucosa (multifocal atrophic gastritis), a pattern long recognized as a risk factor for GC [14, 15]. Autoimmune atrophic gastritis (AIG) is characterized by a spectrum of corpus-restricted lesions including atrophy, extensive pseudopyloric and intestinal metaplasia, and enterochromaffin-like (ECL) cell hyperplasia that coexist with reactive antral changes. The antrum, however, is not affected by either significant inflammation or IM [16, 17]. Since its early descriptions in the XIX century, autoimmune gastritis (particularly when associated with its late consequence, pernicious anemia) has been considered a precancerous condition. However, most studies that detected an increased cancer risk associated with AIG were performed either in the pre-H. pylori era (i.e., before H. pylori was known to exist) or in patients who, unbeknownst to the investigators, may have had H. pylori gastritis and had cleared the infection (spontaneously, incidentally, or by specific treatment) before entering the study. Clearly, such cohorts of subjects with unknown previous or concurrent H. pylori infection were inadequate to provide accurate information on the risk of GC associated with the immunomodulated mechanism of mucosal atrophy at the root of AIG [18]. In a recent long-term follow-up study of a large cohort of patients with AIG and no evidence of current or previous H. pylori infection, we found that the risk for GC was not different from that of the general population of the area [18].

We hypothesized that, if incomplete IM is a more reliable harbinger of GC than its complete counterpart and the only known significant risk factor for GC is H. pylori infection, then the proportion of patients with incomplete IM would be greater in subjects with H. pylori gastritis than in patients with corpus-restricted plausibly autoimmune gastritis. This study was designed to test this hypothesis.

Study Design, Setting, and Data Source

We retrieved gastric biopsies with a histopathologic diagnosis of IM from the IDEA (Inform Diagnostics Electronic Archives), a database containing the records of all patients whose gastrointestinal mucosal biopsies were examined at Inform Diagnostics. During the period covered in this study, all gastric biopsy specimens processed were stained “upfront” with a specific anti-Helicobacter monoclonal immunochemical stain (Cell Marque, Rocklin, CA, USA); most of specimens were also stained with Alcian blue-periodic acid Schiff to enhance the detection of IM. The original diagnosis of the gastric biopsy specimens was made following the guidelines of the Updated Sydney System, the 2002 International Atrophy Consensus [19], and the guidelines proposed in 2005 for reactive gastropathy [20, 21].

Using diagnostic codes and SQL-based natural language queries, we extracted cases that, in addition to IM, had one of the following diagnoses: (1) corpus-restricted atrophic gastritis, likely autoimmune (AIG); (2) H. pylori chronic active gastritis; (3) reactive gastropathy; and (4) patients with IM in an otherwise normal stomach.

Since a diagnosis of corpus-restricted atrophy/inflammation coexisting with normal antral mucosa other than reactive gastropathy is relatively uncommon, all such cases were initially selected. Cases with other entities were selected using a simple random number generator applied to the last 4 digits of each case accession number to extract approximately three times as many H. pylori gastritis and reactive gastropathy as the number of AIG cases and approximately the same number of patients with IM foci in an otherwise normal stomach.

The Inform Diagnostics Internal Review Board determined that this study would be performed by collecting existing data, documents, and reports, that no modifications to the existing diagnoses would be made, and that the information would be recorded in such a manner that subjects cannot be identified. Therefore, pursuant to 45 CFR 46, section 101 b (4) of the Common Code, the study was exempt from 45 CFR 46 regulations, and no informed consent was necessary.

Histopathologic Criteria and Diagnostic Categories

All records originally extracted as potentially consistent with inclusion criteria underwent a histopathologic review of the original slides to: (1) verify the original diagnosis; (2) confirm the presence of the compartmental location (oxyntic vs. antral) of IM; and (3) determine the type (i.e., complete vs. incomplete) and extension (i.e., grade) of IM. After histopathologic review and removal of cases that did not meet the criteria for the study, each biopsy set was assigned to one of the following categories:

Topography of IM

The location (corpus/fundus, i.e., oxyntic, or antrum, i.e., mucosecreting) of the intestinalized epithelium was assessed based on the histologic characteristics of the specimen examined, irrespective of the endoscopist’s definition. Thus, a specimen designated as “antrum” was assigned to the site “corpus” if the pathologist determined it to consist of oxyntic (corpus) mucosa.

Grading of IM

We devised a simple grading system using a slightly modified version of the grading scores recommended by the updated Sydney System [20], which is also compatible with the definitions of “intestinal metaplasia extent” outlined in the 2020 AGA guidelines on gastric IM [6, 7]. Each case was graded on a three-tiered scale: grade 0 (absence of goblet/columnar intestinalized cells). Consistently with the inclusion criteria for this study, no cases in this category were included: grade 1 (G1-IM, less than 30% of intestinalized epithelia, or “limited IM” as defined by the AGA guidelines); and grade 2 (G1-IM, ≥30% of intestinalized epithelia, or “extensive”). An example of G1-IM is depicted in Figure 1.

Fig. 1.

We defined as grade 1 IM (G1-IM) the finding of an isolated metaplastic gland or small groups of metaplastic glands, stained with hematoxylin and eosin (H&E) in panel a and with Alcian blue-periodic acid Schiff (AB-PAS) in panel b. This finding, which may result from the healing of minute gastric mucosal lesions, is usually characterized by a complete-type appearance of the IM and is most common in either normal or minimally inflamed stomachs. Original magnification, ×10 for both images.

Fig. 1.

We defined as grade 1 IM (G1-IM) the finding of an isolated metaplastic gland or small groups of metaplastic glands, stained with hematoxylin and eosin (H&E) in panel a and with Alcian blue-periodic acid Schiff (AB-PAS) in panel b. This finding, which may result from the healing of minute gastric mucosal lesions, is usually characterized by a complete-type appearance of the IM and is most common in either normal or minimally inflamed stomachs. Original magnification, ×10 for both images.

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Subtyping of IM

The recent AGA Technical Report made a simple recommendation: IM that on hematoxylin and eosin staining looks like the small intestine is to be classified as complete, while IM that looks like the colon must be typed as incomplete [22, 23]. Based on these criteria, IM was classified as complete when the epithelium resembled morphologically small intestinal mucosa and was contained absorptive enterocytes with a brush border, Paneth cells, and regularly distributed uniformly sized goblet cells. Incomplete metaplasia was characterized by an epithelium that resembled the colonic mucosa, with secretory nonabsorptive (i.e., without a distinct brush border) columnar cells and more irregularly distributed goblet cells, often of variable size. Figure 2 illustrates the critical aspects of this classification. We find the addition of a combined Alcian blue-periodic acid Schiff to be a useful tool for the rapid visualization of a brush border. In uncertain cases, a CD-10 immunohistochemical stain was used for the more specific detection of the brush border on enterocytes [24]. When complete and incomplete metaplasia coexisted, the case was assigned to the incomplete category and graded accordingly. Using the criteria detailed above, observers determined location, extent, and type of IM while also ensuring that the histopathologic diagnosis provided with each case was correct.

Fig. 2.

Panel a shows a hematoxylin and eosin (H&E) stained section of gastric mucosa with complete IM. The similarity with small intestinal mucosa is even more evident in panel b (stained with Alcian blue-periodic acid Schiff [AB-PAS]), where the orderly distribution of the goblet cells and the brush border are clearly discernible. Panel c shows the brush border stained as a continuous dark line with anti-CD-10 immunohistochemical stain. In contrast, panel d shows the incomplete type of gastric IM. Its colonic appearance (disorderly distribution of goblet cells of variable sizes, absence of brush border) is clearly visible in the AB-PAS section (e). In panel f, a completely negative CD-10 staining confirms the absence of a brush border. Original magnification, ×10 for all images.

Fig. 2.

Panel a shows a hematoxylin and eosin (H&E) stained section of gastric mucosa with complete IM. The similarity with small intestinal mucosa is even more evident in panel b (stained with Alcian blue-periodic acid Schiff [AB-PAS]), where the orderly distribution of the goblet cells and the brush border are clearly discernible. Panel c shows the brush border stained as a continuous dark line with anti-CD-10 immunohistochemical stain. In contrast, panel d shows the incomplete type of gastric IM. Its colonic appearance (disorderly distribution of goblet cells of variable sizes, absence of brush border) is clearly visible in the AB-PAS section (e). In panel f, a completely negative CD-10 staining confirms the absence of a brush border. Original magnification, ×10 for all images.

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The collected histopathologic data were entered into a spreadsheet that contained only one coded patient identifier. Thus, at the time of the slide review, observers were unaware of any demographic, clinical, or previous histopathologic information.

Data Analysis and Statistics

Statistical analyses focused on comparing the relative prevalence of incomplete IM in each of the four groups of subjects and the relationship between subtype and extension of IM. Odds ratios and their 95% confidence intervals were used for all comparisons.

Case Selection and Exclusion

A total of 443 cases were reviewed based on the results of electronic queries. Of these, 27 cases were excluded because the size of the specimens, the quality of the staining, or other technical issues prevented the optimal evaluation of location, extension, and subtype of IM; 14 cases from those with Hp gastritis, reactive gastropathy, and IM in otherwise normal mucosa were excluded because the original diagnosis could not be confirmed with certainty; and 16 cases of presumptive AIG were excluded because of antral metaplasia, inflammation, or insufficient evidence of ECL-cell hyperplasia. This left a total of 386 patients in the study.

Demographics

Basic demographic data of the 386 unique patients included in the study and their respective prevalence of incomplete IM are depicted in Table 1. There were 239 females (61.9%, median age 55 years, range 7–96); 38 of them had incomplete IM (15.9%). Among the 147 males (median age 65, range 15–91), 25 (17.0%) had incomplete IM. The difference between genders was not significant (p = 0.89).

Table 1.

Demographics and prevalence of incomplete IM by diagnostic categories

 Demographics and prevalence of incomplete IM by diagnostic categories
 Demographics and prevalence of incomplete IM by diagnostic categories

Interobserver Variability

To determine the consistency of the evaluation of the IM subtype, a random sample of 40 cases was independently examined by the two main pathologists of the study (RMG and KOT) and scored using a dichotomic scale of complete/incomplete. The consistency between these two observers resulted in a k value of 0.78.

Incomplete Metaplasia in Different Phenotypes of Gastric Mucosa

Table 1 shows the percentage of patients with incomplete IM. Fifty-two of the 138 patients with H. pylori gastritis (37.7%) had incomplete IM. Among the 141 patients with IM arising from reactive gastropathy, 7 (5.0%) had incomplete IM. None of 59 patients with IM micro-foci in a gastric mucosa with no other pathological changes had incomplete IM. Atrophic autoimmune gastritis was associated with incomplete IM in 4 of the 48 patients included (8.3%).

IM Grading and Subtyping

Among the 221 patients with grade 1 IM (G1-IM), 16 subjects had incomplete IM (7.3%) (Table 2). Of these, 12 occurred in H. pylori gastritis, 3 had reactive gastropathy, and one had AIG. Of the 165 patients with grade 2 IM (G2-IM), 47 (28.5%) had incomplete IM; 40 had H. pylori gastritis; 4 had reactive gastropathy; and 3 had AIG. Thus, as shown in Table 3, patients with G2-IM were more than 6 times as likely to harbor incomplete metaplasia as those with G1-IM (odds ratio = 6.69; 95% confidence intervals = 2.77–9.40).

Table 2.

Topographic distribution and extension of IM in different gastric phenotypes

 Topographic distribution and extension of IM in different gastric phenotypes
 Topographic distribution and extension of IM in different gastric phenotypes
Table 3.

Correlation between IM grade and subtype

 Correlation between IM grade and subtype
 Correlation between IM grade and subtype

Location of Incomplete Metaplasia

Patients with small foci of IM, irrespective of their location or etiology, were unlikely to show incomplete IM. Among 209 patients with IM restricted to the antrum (so-called limited according to the AGA definition), only 26 (12.4%) had incomplete IM. In contrast, 25.1% of those with “extensive” IM in the antrum and 26.5% of those with non-focal IM in the corpus had incomplete IM. The strongest predictor of incomplete IM, however, was the simultaneous presence of IM in both the antrum and corpus (38.1%).

Gastric IM, the most common metaplastic change of the gastric glands, may result from injury, likely inflammatory, from both host-related and environmental agents [25]. Since the past century, the “goblet cell columnar” phenotype of intestinalized glands has been linked to the morphogenesis of intestinal-type GC [26, 27]. Several studies have shown a significantly higher cancer risk associated with the so-called incomplete subtype of intestinalized glands. Our study used the recent simplified AGA recommendations to determine the prevalence of different IM subtypes resulting from different etiologies.

IM Subtypes

Among intestinalized glands, the highest risk of neoplastic transformation has been linked to those more closely recapitulating the colonic phenotype. However, it is still debated whether the malignant progeny arises from incomplete-type metaplastic cell clones or from an unstable, mutator phenotype of stem cells triggered by the combined genotoxic effects of H. pylori with the atrophic gastric microenvironment [28]. More than 15 years ago, mutation-prone gastric glands were documented in all the spectrum of gastric advanced precancerous lesions, but no information was available on early precancer [29]. Among 39 cases of IM, the prevalence of a microsatellite stable pattern largely prevailed among complete over incomplete IM (65.8% vs. 34.2%) [28]. In 2015, Li et al. [30] investigated microsatellite instability in gastric precancerous lesions through laser microdissection and showed a mutator phenotype in all six cases of incomplete metaplasia (MSI-l = 2 cases; MSI-H = 4 cases); regrettably, no cases of complete IM were included in their study.

The results of our study indicate that among the gastric conditions in which IM can be found, virtually only H. pylori gastritis shows a significant association with its incomplete subtype, which is consistently associated with a mutator phenotype. In our series, almost 40% of the patients with H. pylori gastritis had incomplete IM, compared with none in those with foci of IM in an otherwise normal mucosa, 5% in those with reactive gastropathy, and 8% in those with AIG. Of the 52 H. pylori-infected patients with incomplete IM, four (8%) were aged between 37 and 47 years, while 72% of them were aged 60 years or older, further confirming the progressive nature of the mucosal damage inflicted by long-standing H. pylori infection. These results strongly suggest an etiological dichotomy between the IM associated with H. pylori gastritis and the IM associated with other gastric conditions, including AIG.

IM Extent and Location

This study provides further evidence for a strong association between the extent of IM and its histological subtyping [10]. Patients with small foci of IM, irrespective of their location or etiology, were unlikely to show incomplete IM, while those with extensive IM, and particularly those with the simultaneous presence of IM in both the antrum and corpus, had a more than 6-fold greater chance of having incomplete IM. In a study of Colombian patients who underwent a comprehensive gastric biopsy protocol, we documented that the topographic spreading (i.e., “extension” or “grade”) of IM involving both gastric compartments significantly correlated with the GC risk, and that in a given stomach, the percentage of incomplete IM was geometrically proportional to the total extension of the IM [12]. These findings are in keeping with the tenets of the OLGA/OLGIM systems; the extension of mucosal atrophy/IM, particularly in the corpus, is the main determinant of the risk for GC [31]. It is worth noting, however, that in all these settings the IM subtype was linked to the cancerogenic model of environmental gastritis, particularly that of H. pylori long-standing infection, where gastric intestinalization proceeds toward the cranial-oxyntic stomach after extensive intestinalization of distal antral mucosa [32‒34].

This study has both limitations and strengths. The number of patients with AIG is relatively small, and their categorization rests entirely on histopathologic criteria since no information about serological data was available. The group of patients with small foci of IM in a gastric mucosa without other detectable pathological changes is likely to be somewhat heterogeneous; in some of them, the focal metaplasia could have resulted from the repair of small lesions due, for example, to chemical irritants, while in other patients, it could represent the sequela of a remotely eradicated H. pylori infection. Irrespective of the cause, however, one can conclude that minor isolated IM foci are rarely, if ever, of the incomplete type. Another significant shortcoming is the paucity of information about patients’ social habits, particularly those suspected of promoting gastric IM, such as the use of alcohol, salt, and tobacco. However, the purpose of this study was to determine the type of IM in subjects with phenotypes of gastritis known to increase the GC risk, not to investigate the causes of IM. Thus, even if this information had been available, it would not have been germane to the scope of this study.

Moreover, the study did not consider the occurrence of pseudopyloric metaplasia, a chief atrophic phenotype within the spectrum of atrophic AIG, also potentially involved in the atrophy spreading to the corpus/fundus as observed in the late-stage H. pylori infection [18]. Another potential drawback is that gastric biopsy sampling was performed based on the clinical judgment of each gastroenterologist who contributed cases, not according to a topographically predefined protocol. Therefore, an element of endoscopic bias is likely to have affected our results, particularly when endoscopists may have sampled areas they thought likely to contain IM.

Although we studied what could be called a “cohort of convenience” (i.e., an existing group chosen because it is available), we selected patients from a large sample in a random fashion, first using queries to extract subjects exclusively based on a diagnosis of IM and the presence of one of the accompanying phenotypes, then selecting cases using a random number generator applied to each specimen’s accession number. Age, gender, and ethnicity were not part of the search criteria. The number of patients for each gastric phenotype was decided in advance in an attempt to represent the proportion of subjects with that phenotype in the electronic archives.

One of the strengths of this study resides in the simple yet accurate and highly reproducible assessment of the IM subtype, which can easily be used by practicing pathologists in their reports of gastric biopsies. By deliberately skipping technically complex and potentially inconsistent cytochemistry staining (high iron diamine) and expensive MUC immunocytochemistry, this study documented the dichotomic association of IM subtypes to different etiologies. In particular, our results validate both the GC risk associated with colonic phenotype as occurring in H. pylori atrophic gastritis and provide support for the recently documented lack of oncogenic risk documented in a large cohort of AIG patients followed up with paired biopsy for a median of 7 years [18].

Clinicians who wisely rely on histology reports to manage their patients should cooperate with pathologists in promoting a clinically relevant histology reporting. This can be achieved by submitting biopsy sets that allow for the determination of the OLGA/OLGIM gastritis stage (which includes IM subtyping) and requesting their pathologists to generate reports that include both gastritis stage and IM subtyping [35].

This was an analysis of existing data. No contact with patients or doctors was made, and no diagnostic changes were made to the original diagnoses. All data were deidentified prior to analysis. No consent from subjects was necessary.

Authors who either are or were employees of Inform Diagnostics, Irving, Texas, at the time of the study (Robert Maximilian Genta, Kevin Orlando Turner, Anuradha Singhal, and Cristian Robiou) received no payment to either perform this study or to write this manuscript; they declare no relevant conflicts of interest. Massimo Rugge has no conflicts of interest.

No financial support from any source was received for the performance of this study.

Robert Maximilian Genta and Massimo Rugge designed the study, analyzed the data, and wrote the manuscript. Robert Genta is the guarantor of the article. Kevin Orlando Turner searched, extracted, and organized patients from the database. Anuradha Singhal supervised the utilization of the database, coordinated the release and examination of the histology slides and other material, and participated in the evaluation of the slides. Cristian Robiou participated in the conception and design of the study and evaluated a portion of the slides. All authors generated data, participated in the planning of the study, and approved the final version of the manuscript.

The databases used to extract the case studies contain private and sensitive patient information and cannot be made public as per HIPAA rules. However, relevant deidentified data may be made available upon request.

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