Unmasking the high-risk phenotype in autoimmune gastritis: A pathologist’s roadmap for the clinician

Abstract

Li et al’s recent work on the risk factors for autoimmune gastritis provides clinical context for the vast majority of gastric neuroendocrine tumors (G-NETs). However, a deeper understanding of the underlying pathology is needed for precise clinical management. Our letter details the predictable stepwise progression of type 1 G-NETs from autoimmune-driven corporal atrophy and hypergastrinemia to a clear microscopic sequence of enterochromaffin-like cell precursor lesions, including linear hyperplasia, micronodular hyperplasia, and dysplasia. We highlight the definitive diagnostic thresholds that separate these precursors from overt neoplasia: The 0.5 mm size rule and the presence of submucosal invasion. We advocate for a “prognostic biopsy protocol” in which pathologists actively report these precursor lesions and use Ki-67 to grade G-NETs, providing a quantitative risk assessment. This pathology-centric approach transforms surveillance, allowing clinicians to act on objective microscopic milestones rather than waiting for macroscopically visible tumors.

Key Words: Pathology; Autoimmune gastritis; Gastric neuroendocrine tumors; Precursor lesions; Dysplasia

Core Tip: Clinical risk models identify patients with autoimmune gastritis who may develop neuroendocrine tumors, but pathology guides what to do next. We advocate for a “prognostic biopsy protocol” where pathologists report the specific stage of microscopic pre-cancerous lesions. Finding high-risk changes, especially dysplasia, serves as a clear trigger to intensify surveillance. This approach allows clinicians to manage risk proactively based on a patient’s real-time biology, rather than waiting for a visible tumor to develop.

TO THE EDITOR

We have read with interest the article by Li et al[1] in the World Journal of Gastroenterology. Their analysis of 303 patients produced an effective predictive model incorporating five clinical and endoscopic features, providing a strong scientific basis for risk stratification. Although invaluable for identifying at-risk individuals, we aimed to explore how these findings can be combined with pathological data to guide a more dynamic and actionable approach to patient surveillance.

BEYOND ENDOSCOPY: DEFINING NEOPLASTIC RISK THROUGH PATHOLOGICAL CORRELATION

Endoscopic evaluation provides the initial evidence for the diagnosis of autoimmune gastritis (AIG). The hallmark endoscopic finding is “reverse atrophy”, characterized by a pale, thinned corpus mucosa with effacement of rugal folds and increased visibility of the submucosal vascular pattern[2-4]. Histologically, these macroscopic features directly correlate with the extensive loss of oxyntic glands, which are frequently replaced by fibrosis and metaplastic epithelium, such as the intestinal or pseudopyloric types[3,5,6]. While endoscopy identifies this high-risk atrophic field, visible changes represent only a fraction of the underlying pathology. The full spectrum of neoplastic risk is discernible only through microscopic examination of the tissue.

The primary targets for biopsy are discrete mucosal lesions such as nodules or polyps. Such lesions, often appearing as small erythematous nodules, are present in more than 10% of patients with AIG; however, their endoscopic morphology is non-specific and insufficient for diagnosis[7,8]. Histopathological assessment is indispensable for differentiating benign entities, such as hyperplastic or pseudopolyps, from incipient grade 1 gastric neuroendocrine tumors (G-NETs)[8,9]. Given that even diminutive nodules may harbor well-differentiated neoplasia, it is an established principle that any distinct nodularity within the atrophic corpus of a patient with AIG warrants targeted biopsy[5,10].

However, the most significant prognostic information often resides within the endoscopically unremarkable flat atrophic mucosa. Within this background milieu, precursor lesions of G-NETs develop, often without overt endoscopic signs. These microscopic alterations, encompassing a well-defined spectrum of enterochromaffin-like (ECL) cell proliferation from linear hyperplasia to micronodular hyperplasia, and ultimately dysplasia, are the most powerful predictors of subsequent tumor development[3,5]. The identification and grading of these occult lesions are exclusively within the purview of the pathologist. This process translates general endoscopic observations into a specific biological risk profile, thereby facilitating precise and actionable assessment of the patient’s neoplastic risk.

THE PATHOGENIC CONTINUUM: FROM HYPERGASTRINEMIA TO NEOPLASIA

In AIG, autoimmune-mediated destruction of parietal cells results in achlorhydria and consequent compensatory hypergastrinemia[11,12]. Sustained hypergastrinemia exerts a potent trophic effect on ECL cells and induces a well-defined spectrum of precursor lesions. This histopathological continuum, first identified by Solcia et al[13], progresses sequentially from linear hyperplasia to micronodular and adenomatoid hyperplasia, ultimately culminating in ECL cell dysplasia, as illustrated in Figure 1.

Figure 1 The histopathologic spectrum of enterochromaffin-like cell proliferation in autoimmune gastritis. The figure illustrates the sequential, gastrin-driven progression from normal gastric mucosa to high-risk dysplastic precursor lesions using schematic representations (top row) and corresponding synaptophysin immunohistochemistry (bottom row). Beginning with the normal state of scattered, single enterochromaffin-like cells in the glandular base, the earliest proliferative change is linear hyperplasia, characterized by chains of five or more cells. This progresses to micronodular hyperplasia, where small, cohesive clusters (< 150 μm) form, which then advance to adenomatoid hyperplasia through the coalescence of multiple micronodules in the deep lamina propria. The sequence culminates in dysplasia, the immediate precursor to neoplasia, identified by enlarged, fused, and architecturally complex nodules with micro-infiltrative patterns that efface the normal glandular structure; this stage can be accompanied by the formation of new stroma (depicted in light blue). All images in the bottom row are stained for synaptophysin (brown). All scale bars represent 50 μm. Syn: Synaptophysin; ECL: Enterochromaffin-like.

Although low-grade hyperplasia is a common finding, the development of advanced precursor lesions represents a critical inflection point in neoplastic risk. Specifically, the presence of severe hyperplasia, or most significantly ECL cell dysplasia, are powerful independent predictors of G-NET development[14]. The identification of dysplasia, a lesion characterized by increased architectural complexity, is particularly ominous, elevating the risk of tumor development by more than 20-fold[15-17].

Crucially, the diagnostic threshold for an overt Type 1 G-NET is not subjective, but is defined by objective size-based criteria according to World Health Organization (WHO) guidelines: The presence of a lesion exceeding 0.5 mm in diameter or one that has invaded the submucosa[14,18]. Therefore, a gastric biopsy provides far more than a binary assessment of malignancy. It offers a definitive staging of the precursor field, effectively locating the patient along this well-defined carcinogenic pathway and enabling a risk assessment with greater precision than can be achieved using clinical features alone.

THE PROGNOSTIC BIOPSY PROTOCOL: A PATHOLOGY-CENTRIC SURVEILLANCE STRATEGY

The predictive model developed by Li et al[1] provides an effective framework for identifying patients with AIG who have entered a well-documented continuum toward neuroendocrine neoplasia. To translate this risk stratification into a precise clinical management, we recommend the use of a “prognostic biopsy protocol”. In this pathology-centric framework, histopathological analysis translates endoscopic findings into actionable prognostic indicators. Therefore, gastric biopsy is not merely a diagnostic sample, but also an essential tool for biological staging, providing a definitive assessment of the patient’s exact position along the neoplastic pathway.

This trajectory is marked by distinct histological milestones that, when actively reported by a pathologist, signify escalating risk. The presence of linear and micronodular hyperplasia confirms that the gastrin-driven proliferative process is active and validates the need for continued surveillance[18]. Critical progression is marked by adenomatoid hyperplasia, which represents the coalescence of precursor lesions. The final and most significant prognostic threshold is the identification of ECL cell dysplasia, characterized by fused micronodules or micro-infiltrative architectural patterns[18]. As the immediate precursor to invasive neoplasia, the discovery of dysplasia should trigger a more intensive surveillance plan, a recommendation justified by evidence that established G-NETs are consistently associated with such high-risk changes in the background mucosa[15,19,20]. While our histopathological framework provides a biological rationale for this intensification, defining precise evidence-based surveillance intervals for these high-risk patients remains a critical challenge for prospective clinical studies and guideline committees.

Once an overt G-NET is diagnosed, its biological potential must be formally graded to provide a quantitative risk assessment. This objective measure of proliferation, determined by mitotic count and Ki-67 labeling index, is the cornerstone of the WHO grading system[18]. A report of a grade 1 G-NET (Ki-67 < 3% and mitotic count < 2/2 mm²) defines an indolent neoplasm with low metastatic potential, accounting for the vast majority of tumors in the AIG setting. Conversely, grade 2 G-NETs (Ki-67 3%-20% and mitotic count 2/2 mm² to 20/2 mm²) represent a tumor with more aggressive biological behavior, necessitating more comprehensive staging and management.

This pathology-centric framework empowers clinicians to act on objective microscopic milestones rather than waiting for the development of macroscopically visible tumors. It fundamentally shifts the paradigm of patient management from a static, interval-based strategy to a dynamic, risk-adapted approach in which clinical decisions are precisely tailored to the evolving biological landscape of the patient.

CONCLUSION

In summary, the neoplastic risk of AIG is best managed using a histopathologically guided dynamic surveillance strategy. The well-defined spectrum of ECL cell precursor lesions provides clear, actionable thresholds for clinical decision making. The identification of high-risk changes, such as dysplasia, should prompt the immediate intensification of surveillance. This framework, which pairs the staging of precursor lesions with the definitive grading of overt G-NETs, allows for a rational, biology-driven approach that is superior to static protocol-based monitoring.