Introduction

Helicobacter pylori is a gram-negative bacterium that colonizes the gastric mucosa of the human stomach and plays a significant role in the development of various gastrointestinal disorders, including gastric ulcers, gastric cancer, chronic active gastritis, and mucosa-associated lymphoid tissue lymphoma [1]. The bacterium’s ability to persist in the harsh acidic environment of the stomach is facilitated by its microaerophilic nature and production of urease, which neutralizes stomach acid. Studies have shown that H. pylori is not confined to the gastric lumen and is capable of invading deeper layers of the gastric mucosa, including the epithelial cells and lamina propria, and even translocating to the gastric lymph nodes [2-5]. The ability to invade and persist in deeper mucosal layers complicates both diagnostic and treatment strategies, highlighting the need for sensitive diagnostic methods.

The incidence of H. pylori infection varies across regions, with higher prevalence reported in developing countries. Factors, such as geographic location, age, socioeconomic status, and healthcare accessibility, contribute to these differences. In Thailand, the prevalence of H. pylori infection is 45.9%, as determined by immunohistochemistry (IHC) [6]. Accurate diagnosis is essential for effective patient management, especially for preventing long-term complications associated with chronic infections.

The standard diagnostic methods for detecting H. pylori infection include the rapid urease test (RUT), histological examination, and bacterial culture [7,8]. RUT is commonly used because of its rapid turnaround time (1–24 hours) and utility in epidemiological studies. This test detects the urease activity of H. pylori, which hydrolyzes urea into ammonia and bicarbonate, resulting in a visible color change. However, the sensitivity of RUT can be affected by several factors including the use of proton pump inhibitors (PPIs), antibiotics, and bismuth compounds, all of which suppress urease activity. Additionally, non-H. pylori urease-producing bacteria, such as Proteus mirabilis and Klebsiella pneumoniae, may lead to false-positive results, further complicating the diagnostic process [9,10].

In contrast, IHC has shown superior sensitivity and specificity compared to conventional histochemical staining methods, making it the preferred technique for identifying H. pylori in gastric biopsies [11-13]. IHC is especially effective for detecting the bacteria in inflamed tissues and their coccoid form, which can be challenging to differentiate from cellular debris using standard staining techniques. Furthermore, IHC allows the visualization of H. pylori within different layers of gastric mucosa, offering significant diagnostic and therapeutic implications. Notably, studies by Ito et al. [5] using the TMDU monoclonal antibody (Medical & Biological Laboratories [MBL], Nagoya, Japan) have demonstrated that H. pylori can invade beyond the surface epithelium into the lamina propria and even translocate to the gastric lymph nodes, emphasizing the need for diagnostic techniques capable of detecting such deeper infections.

While various monoclonal and polyclonal antibodies are available for the IHC detection of H. pylori, their diagnostic performance can vary based on bacterial location within the gastric tissue. Some antibodies are more effective at detecting H. pylori in the surface epithelium, whereas others identify bacteria in the subepithelial layers, offering a more comprehensive understanding of the infection [5]. Thus, combining IHC with RUT may provide a more holistic approach for diagnosing H. pylori infections, particularly in cases in which bacterial localization and mucosal changes influence disease progression.

The primary objective of this study was to evaluate the diagnostic performance of IHC and RUT in detecting H. pylori in gastric biopsies from patients with gastroduodenal symptoms. We assessed the sensitivity and specificity of these methods by focusing on bacterial localization (epithelial vs. subepithelial regions) and histopathological changes in the gastric mucosa. Additionally, we explored how bacterial location and mucosal alterations influenced the diagnostic accuracy of both RUT and IHC in clinical practice.

Methods

Ethics statement: The study protocol was reviewed and approved by the Institutional Ethics Committee of Vajira Hospital, Faculty of Medicine, Navamindradhiraj University (ethics code: 119/66) and patient consent was waived by the Institutional Ethics Committee. The research was conducted on archival, anonymized tissue.

1. Study design and setting

This retrospective study was conducted at Vajira Hospital, Faculty of Medicine, Navamindradhiraj University, Bangkok, Thailand, over a 7-month period, from June 2022 to December 2022.

2. Patient selection

Patients who presented with upper abdominal symptoms and underwent upper gastrointestinal endoscopy were screened for inclusion. The inclusion criteria were as follows: (1) availability of at least four gastric biopsy specimens obtained from both the antrum and corpus per standard clinical practice and (2) adequate formalin-fixed, paraffin-embedded (FFPE) tissue for both hematoxylin and eosin (H&E) staining and IHC analysis. The exclusion criteria included: (1) inadequate biopsy material or suboptimal tissue preservation preventing reliable histopathological evaluation, (2) age ≤18 years, (3) use of medications such as PPIs, H2-receptor antagonists, bismuth compounds, antibiotics, nonsteroidal anti-inflammatory drugs, and (4) H. pylori eradication therapy within 1 month prior to endoscopy.

Only patients who underwent gastric biopsy and RUT during the same endoscopic procedure were included in the final analysis.

3. Histopathology

All FFPE tissue blocks were sectioned at 3-μm thickness and stained with H&E. Two pathologists (CS and KL) independently examined the H&E-stained sections. In cases of discrepant interpretation, the slides were reviewed together, and a consensus diagnosis was established through discussion.

Histopathological features, including neutrophilic and mononuclear inflammation, glandular atrophy, and intestinal metaplasia, were assessed and graded on a 4-point scale (0, none; 1, mild; 2, moderate; 3, severe) according to the Updated Sydney System [14].

Gastritis was classified based on the type of inflammatory response (chronic and/or active) and the presence or absence of morphological changes such as intestinal metaplasia, glandular atrophy, or ulceration. Based on these criteria, the patients were categorized into one of the following four diagnostic groups: (1) chronic nonactive gastritis without morphological changes, (2) chronic active gastritis without morphological changes, (3) chronic nonactive gastritis with morphological changes, or (4) chronic active gastritis with morphological changes.

4. Rapid urease test

The RUT was performed using the Pronto Dry kit (GASTREX, Brignais, France). Gastric mucosal biopsies were obtained from the antrum, approximately 2 to 3 cm proximal to the pyloric ring, by following the standard endoscopic protocol. In cases where corpus involvement was suspected, an additional biopsy from the corpus was placed on the test medium. The biopsy specimens were applied directly to the urea/indicator-impregnated filter paper on the test card. The results were interpreted by observing the color change from yellow to red, which indicates an increase in pH due to urease activity. The color was assessed at 15, 30, and 60 minutes. A positive result within 30 minutes indicated a high bacterial load. Negative results after 60 minutes were considered reliable in the absence of PPI use or recent antibiotic therapy. All the test kits were stored and handled under the recommended temperature and humidity conditions specified by the manufacturer.

5. Immunohistochemistry

IHC was performed on 2-μm-thick FFPE gastric tissue sections using a Leica Bond-Max automated platform (Leica Microsystems, Buffalo Grove, IL, USA).

Deparaffinization and rehydration were performed automatically using Bond Dewax and Bond Wash Solutions (Leica Microsystems). Antigen retrieval was performed using Epitope Retrieval Solution 2 (ER2, pH 9.0; Leica Microsystems) at 100°C for 20 minutes. Endogenous peroxidase activity was blocked using a 3% hydrogen peroxide solution at room temperature for 5 minutes. The following primary antibodies against H. pylori were used: mouse monoclonal antibody TMDU-D8 (1:800, MBL #D369-3; MBL), mouse monoclonal antibody ULC3R (1:300, BioGenex #MU880-5UCE; BioGenex, Fremont, CA, USA), rabbit polyclonal antibody #215A-76 (1:100; Cell Marque, Rocklin, CA, USA), and rabbit polyclonal antibody #B0471 (1:50; Dako, Carpinteria, CA, USA). Detection was performed using the Bond Polymer Refine Detection kit (DS9800; Leica Biosystems), and the slides were counterstained with hematoxylin, dehydrated, and covered with coverslips. Observations were performed using a standard bright-field light microscope. Positive controls consisted of known H. pylori-infected gastric tissues, whereas negative controls consisted of gastric tissues from patients with no histological evidence of gastritis who had received sleeve gastrectomy.

6. Detection of Helicobacter pylori

A case was defined as H. pylori-positive when at least one monoclonal IHC antibody demonstrated consistent positive staining, either epithelial or subepithelial immunoreactive signals. This composite approach provided high sensitivity and specificity in the absence of a universally accepted gold standard. Notably, monoclonal antibodies, particularly those from BioGenex or MBL, offer enhanced specificity over polyclonal antibodies, making the former more reliable indicators of true infection.

Although both polyclonal and monoclonal antibodies may exhibit cross-reactivity with Helicobacter heilmannii, morphological assessments were performed to confirm species identity. Organisms detected by IHC were carefully examined under light microscopy at 400× or higher magnification to exclude the presence of H. heilmannii. Organisms exhibiting corkscrew morphology and a length greater than 3 µm were excluded from analysis [15].

The surface epithelial density of H. pylori was graded according to the Updated Sydney System standardized visual analog scale, which classifies bacterial presence into four categories: S0 (no bacteria), S1 (mild; individual bacteria or small clusters occupying less than one-third of the mucosal surface), S2 (moderate; greater density than mild but less density than severe), and S3 (severe; large clusters of bacteria covering more than two-thirds of the mucosal surface) [14].

Subepithelial H. pylori localization, including intracellular and interstitial localization, was evaluated at high magnification (0.196 mm² per high-power field) using a Nikon Eclipse E200 light microscope (Nikon Corp., Tokyo, Japan). The basement membrane served as the histological reference point, and only the signals located beneath it were counted. To define subepithelial colonization of H. pylori, only immunoreactive signals meeting stringent spatial, morphological, and immunohistochemical criteria were included. Signal inclusion required immunoreactivity comparable in intensity to surface-attached bacilli seen in positive internal or external controls and the absence of staining in negative controls to confirm specificity and exclude nonspecific background. Homogeneous or indistinct clumps were recorded as a single signal, whereas well-defined discrete signals within a clump were counted individually. In cases where the signal density varied across the slide, the region with the highest density (“hotspot”) was selected for evaluation. Morphologically, acceptable signals appeared as uniform, dot-like, non-refractile structures, typically 0.5 to 1.5 µm in diameter (consistent with coccoid or degenerated forms of H. pylori), while signals with atypical features, such as those with elongated, fragmented, amorphous, or smeared morphologies, were excluded due to the likelihood of representing fixation artifacts, cellular debris, or background chromogen granules. Only discrete well-circumscribed signals were considered reliable. Particular attention was given to the distribution pattern; signals arranged in clusters or focal aggregates were favored, as these configurations supported the biological plausibility of localized bacterial colonization. Linear arrangements along glandular structures or within the lamina propria were accepted if they were morphologically consistent and spatially coherent. Single isolated signals were included only when they demonstrated unequivocal morphology and strong staining intensity, were located outside artifact-prone zones, and appeared in the context of inflammation or accompanying surface colonization. In contrast, signals displaying random, scattered, or diffuse background positivity without a clear morphological definition were excluded, as they likely represented nonspecific staining, chromogen deposition, or technical artifacts.

Additionally, to avoid misclassification due to sectioning artifacts, care was taken to distinguish true subepithelial colonization from organisms artificially displaced by tangential or oblique sectioning of the surface epithelium. This misorientation can create a false impression of bacilli located beneath the basement membrane. Therefore, subepithelial signals were only observed when the mucosa was sectioned in an orientation that clearly delineated the epithelial-stromal interface, with the basement membrane identifiable in the perpendicular cross-section. Signals adjacent to poorly oriented or folded epithelium, or in regions suggestive of tangential sectioning, were excluded unless confirmed in serial sections and supported by the corresponding inflammatory context or reproducibility.

To confirm the reliability of ambiguous findings, all cases showing uncertain or borderline subepithelial staining were sectioned and stained again using the same IHC protocol. Staining was repeated using fresh internal positive and negative controls to ensure antibody specificity and consistency. The original and repeated slides were reviewed side-by-side by two independent pathologists. Only cases in which subepithelial signals were reproducible in terms of morphology, location, and staining intensity were included in the analysis. Cases that failed to show consistent findings were excluded, thereby minimizing false positives due to technical or interpretive artifacts. For quantification, the number of valid subepithelial signals per high-power field (0.196 mm²) was graded as follows: I0 (no signal), I1 (1–20 signals), I2 (21–50 signals), and I3 (>50 signals). To further reduce false positives, signals confined to regions prone to artifacts, such as biopsy edges, tissue folds, or cautery-affected areas, were not included. Collectively, these comprehensive criteria ensured accurate identification of true subepithelial H. pylori colonization, distinct from background noise or nonspecific immunostaining.

7. Statistical analysis

The sensitivity and specificity of each diagnostic modality were calculated using a composite reference standard for H. pylori positivity. Associations between histological features and diagnostic outcomes were analyzed using the chi-square test. The McNemar test was used to compare the sensitivity of the paired diagnostic methods applied to the same set of patients. This test evaluates the statistical significance of discordant results (i.e., cases that are positive by one method but negative by another), allowing for a comparison of paired binary outcomes. A p-value <0.05 was considered statistically significant. All the analyses were performed using Stata version 13 (StataCorp LLC, College Station, TX, USA).

Results

1. Detection rates of Helicobacter pylori by diagnostic method

Table 1 summarizes the overall detection rates of H. pylori using the five diagnostic modalities: RUT and IHC with BioGenex, MBL, Cell Marque, and Dako antibodies. Among these, IHC with the BioGenex antibody had the highest detection rate, identifying H. pylori in 70 cases (52.6%), followed by IHC with the MBL (52 cases, 39.1%), Cell Marque (38 cases, 28.6%), and Dako (34 cases, 25.6%) antibodies. RUT exhibited the lowest sensitivity, detecting H. pylori in only 33 cases (24.8%).

2. Surface bacterial densities

Surface colonization was semi-quantitatively graded as mild (S1+), moderate (S2+), or marked (S3+). IHC with the BioGenex antibody detected surface H. pylori at mild, moderate, and marked densities in 12.8%, 6.8%, and 9.0% of the cases, respectively. The MBL antibody exhibited comparable surface detection at frequencies of 10.5% (S1+), 4.5% (S2+), and 10.5% (S3+). The Cell Marque and Dako antibodies exhibited comparable results, albeit with slightly lower overall detection rates.

3. Subepithelial bacterial densities

Distinct differences were observed in the subepithelial detection capabilities of these methods. IHC with the BioGenex antibody identified mild (I1+), moderate (I2+), and marked (I3+) bacterial densities in 24.8%, 14.3%, and 11.3% of the cases, respectively. In contrast, the MBL antibody detected 24.1% of the cases at I1+, 6.0% at I2+, and none at I3+. Notably, the BioGenex antibody detected all MBL-positive cases in the subepithelium, indicating its superior sensitivity. The Cell Marque and Dako antibodies were significantly less sensitive in the subepithelial compartment, with only 1.5% of the cases showing I1+ density and no moderate or marked detection. These findings emphasize the enhanced sensitivity of the BioGenex antibody, particularly in detecting H. pylori in deeper mucosal compartments, which are often missed by other methods.

4. Diagnostic accuracy compared to reference standards

Using the MBL antibody as the reference standard (Table 2), the BioGenex antibody achieved perfect sensitivity (100%) and a negative predictive value of 100%, although its specificity was moderate (77.8%), indicating a higher false-positive rate. The RUT exhibited moderate sensitivity (55.8%) and high specificity (95.1%). IHC with the Cell Marque and Dako antibodies exhibited excellent specificity (98.8%) and a high positive predictive value (PPV) but lower sensitivities (71.2% and 63.5%, respectively). When the BioGenex antibody was used as the gold standard, the MBL antibody achieved high sensitivity (74.3%), and perfect specificity (100%) and PPV (100%). RUT and IHC with the Cell Marque and Dako antibodies demonstrated limited sensitivity, reinforcing the superior diagnostic performance of the BioGenex antibody.

5. Distribution of bacterial densities in surface and subepithelial regions

Table 3 presents a detailed breakdown of H. pylori bacterial densities according to the location and method. In 52 MBL antibody-positive cases, surface staining was absent in 34.6% of cases, with mild, moderate, and marked densities detected in 26.9%, 11.5%, and 26.9% of cases, respectively. Subepithelial staining was identified at moderate density (61.5% of cases) with this antibody.

Among the 70 BioGenex antibody-positive cases, surface detection was absent in 45.7% of them, while 24.3%, 12.9%, and 17.1% of cases showed mild, moderate, and marked positivity, respectively. The BioGenex antibody was especially effective in detecting subepithelial colonization, with 47.1% and 21.4% of cases showing moderate and marked densities, respectively, significantly outperforming the other antibodies.

In the combined RUT-positive, MBL antibody-positive, and BioGenex antibody-positive cases (n=29), both surface and subepithelial colonization were detected at higher densities, particularly by the BioGenex antibody. In contrast, among the RUT-negative but MBL and BioGenex antibody-positive cases (n=23), the BioGenex antibody alone frequently identified high subepithelial bacterial loads that were otherwise missed.

Subgroup analysis also revealed that the BioGenex antibody retained its superior sensitivity across various combinations of antibody positivity (e.g., Cell Marque antibody-negative or Dako antibody-negative), consistently detecting marked subepithelial density in ≤36.8% of cases.

6. Sensitivity across histological subgroups

Table 4 outlines the sensitivity of each diagnostic method across the histological categories of H. pylori-positive gastritis. IHC with the BioGenex antibody consistently showed 100% sensitivity in all the groups, including those with chronically nonactive or morphologically subtle gastritis. The MBL antibody also performed well, particularly in cases of active gastritis, achieving 100% sensitivity for classes 3 and 4.

In contrast, RUT demonstrated low sensitivity in cases without active inflammation or morphological changes, dropping to 28.6% in class 1. The Cell Marque and Dako antibodies also underperformed in these contexts, with sensitivity of the latter as low as 10.7% in class 2. The McNemar test confirmed the statistical superiority of IHC with the BioGenex antibody over all other methods (p<0.05).

Discussion

This study assessed the diagnostic performance of IHC techniques and RUT for detecting H. pylori, with an emphasis on bacterial localization (surface vs. subepithelial) and the presence or absence of mucosal changes.

RUT remains a widely used method owing to its simplicity and cost-effectiveness; however, its sensitivity is closely tied to bacterial location and gastric mucosal state. It performed well in detecting surface-attached H. pylori, in which urease activity is typically concentrated. In contrast, its sensitivity significantly declined when the bacteria were located in the subepithelial layer or when mucosal inflammation was minimal. This limitation was most pronounced in chronic nonactive gastritis without morphological changes, where the bacterial density was low and the localization was deeper, leading to a substantial drop in RUT detection rates.

IHC methods, particularly using the BioGenex antibody, demonstrated superior diagnostic performance across all histological subgroups. Unlike RUT, IHC is not dependent on bacterial urease activity and can detect organisms even at low densities or in morphologically subtle infections. The BioGenex antibody showed 100% sensitivity in detecting both surface and subepithelial H. pylori, outperforming the MBL antibody and RUT, particularly in challenging cases.

A notable finding of this study was the clear identification of an isolated subepithelial pattern of H. pylori colonization, which was detected far more effectively by the BioGenex antibody. While both BioGenex and MBL antibodies performed similarly in epithelial regions, the former identified moderate-to-marked subepithelial H. pylori in 34 of 67 cases, compared to only 8 of 40 cases identified by the MBL antibody. IHC with the BioGenex antibody detected all subepithelial cases identified by the MBL antibody, indicating superior sensitivity. Additionally, the BioGenex antibody detected H. pylori in 32 cases without any surface staining, compared to 18 cases for the MBL antibody, and identified 14 additional subepithelial-positive cases that were negative for the MBL antibody. These results were validated by the absence of surface staining across four different IHC markers, underscoring the importance of subepithelial detection (Fig. 1).

This observation introduces an important diagnostic and biological concept: unlike surface-attached bacilli, subepithelial H. pylori often presents as dot-like signals, which may represent bacterial casts or coccoid forms. However, these forms have several clinical considerations. First, they could reflect residual bacteria in unbiopsied regions, which are potentially viable and capable of causing reinfection. Second, they may represent a morphological transformation from typical bacillary to coccoid forms in response to stress. These coccoid forms may remain undetected by conventional methods, exhibit reduced urease activity (potentially leading to false-negative results by RUT), evade immune surveillance, and revert to culturable bacilli, contributing to treatment failure or relapse [16-19]. Although it remains uncertain whether these subepithelial signals represent viable organisms or remnants of dead bacteria, their consistent detection by IHC underscores their diagnostic relevance. This finding supports the need for additional noninvasive testing, such as the urea breath test or stool antigen test, to confirm the infection status, consistent with current clinical guidelines [20].

From a clinical standpoint, the inability of RUT to detect subepithelial H. pylori presents a risk of underdiagnosis, especially in patients with nonactive or morphologically normal gastric mucosa.

The comparative analysis across histological subgroups further highlights the limitations of RUT. For instance, in chronic nonactive gastritis without morphological changes, RUT had a sensitivity of only 28.6%, compared to 100% for the BioGenex antibody, with a statistically significant difference (p<0.05). Similarly, the surface vs. subepithelial analysis showed that the sensitivity of RUT for surface infections was 68.4%, which was significantly lower than that of the MBL (89.5%) and BioGenex (100%) antibodies. IHC with the BioGenex antibody also achieved 98.5% sensitivity in detecting subepithelial H. pylori. Statistical analysis using the McNemar test confirmed that these differences were significant across several key histological categories. These findings underscore the limited diagnostic reliability of RUT, especially in less active or morphologically unremarkable gastritis, and highlight the superiority of IHC-based detection.

In conclusion, IHC with the BioGenex antibody offers superior sensitivity for detecting H. pylori, particularly in the subepithelial regions that are often missed by RUT or less sensitive IHC methods. It is the most effective tool for identifying H. pylori in both surface and subepithelial locations. To ensure comprehensive diagnosis and effective treatment, patients with suspected subepithelial H. pylori infection should undergo additional evaluation using urea breath tests or stool antigen tests, as recommended by current clinical guidelines.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization, Formal analysis, Methodology, and Supervision: KL; Data curation, Visualization, and Validation: CS; Writing-original draft: all authors; Writing-review & editing: CS.

Fig. 1.

Distribution of immunoreactive Helicobacter pylori in surface epithelial and subepithelial locations, detected using four antibodies: BioGenex, MBL, Cell Marque, and Dako. Although detection frequency and staining intensity of H. pylori in the surface epithelium are comparable across all four antibodies, notable differences are observed in the immunohistochemical detection of subepithelial H. pylori within the lamina propria. Scattered dot-like particles are observed with (A) BioGenex and (B) MBL, whereas no such particles are detected with (C) Cell Marque or (D) Dako. Isolated subepithelial immunoreactive signals are exclusively detected by (E) BioGenex and (F) MBL, whereas (G) Cell Marque and (H) Dako fail to reveal any such signals. Unlike surface-attached bacilli, subepithelial H. pylori typically appear as dot-like structures, possibly representing bacterial casts or coccoid forms. Notably, none of the antibodies detect surface-attached bacteria in the subepithelial compartment, emphasizing the distinct and isolated nature of subepithelial colonization. All images were captured at 60× magnification, providing detailed visualization of bacterial localization. BioGenex: Fremont, CA, USA; Medical & Biological Laboratories (MBL): Nagoya, Japan; Cell Marque: Rocklin, CA, USA; Dako: Carpinteria, CA, USA.

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Figure & Data

References

Citations

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