Authors: Kush Fansiwala (1.Department of Internal Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA), Michael S. Lewis (2.Departments of Medicine and Pathology, Cedars Sinai Medical Center, Los Angeles, CA, 90048, USA; 3.Department of Pathology, VA Greater Los Angeles Medical Center, Los Angeles, CA, 90073, USA), Joseph R. Pisegna (4.Division of Gastroenterology, Hepatology and Parenteral Nutrition, Dept of Medicine VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA; 5.Department of Human Nutrition David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA)
Categories: Article
Source: The American journal of gastroenterology
Authors: Kush Fansiwala, Michael S. Lewis, Joseph R. Pisegna
The term “gastritis” is commonly used incorrectly to describe the clinical syndrome of dyspepsia or endoscopic findings of gastric inflammation, but is formally defined as any inflammation of the gastric mucosa confirmed on histology.^1^ Gastritis exists on a spectrum of disease and understanding the concepts of atrophic gastritis and intestinal metaplasia are key to understanding the severity.
When approaching the characterization of gastritis, the first key branch point is the presence of atrophy, defined as loss of appropriate glandular structures of the oxyntic mucosa.^2^ Atrophy can result from replacement of the glands with fibrosis of the lamina propria or with metaplastic glandular structures, known as intestinal metaplasia. Intestinal metaplasia is defined as replacement of gastric columnar cells by cells of intestinal morphology, characterized by the presence of mucin-containing goblet cells, Paneth cells, and absorptive cells.^3^ The presence of atrophic gastritis and intestinal metaplasia portend the potential for transformation to gastric cancer.
The predominant concern for prolonged gastritis is the risk of intestinal-type gastric cancer development. In 1975, Correa et. al postulated that there was a progressive, stepwise pathway for gastric carcinogenesis, titled the “Correa Cascade”. This stepwise series was refined to the normal gastric mucosa → non-atrophic gastritis → multifocal atrophic gastritis without intestinal metaplasia → intestinal metaplasia of the complete (small intestine) type → intestinal metaplasia of the incomplete (colonic) type → low-grade dysplasia (low-grade noninvasive neoplasia) → high-grade dysplasia (high-grade noninvasive neoplasia) → invasive adenocarcinoma.^4^ Several large studies have supported the increased risk of gastric cancer with the presence of more advanced lesions in the cascade.^5, 6^
While chronic gastritis most commonly is associated with gastric adenocarcinoma, there is an important relationship between gastritis and gastric neuroendocrine tumors (GNETs). While GNETs are overall rare, type 1 GNETs commonly arise in the setting of chronic corpus-involving atrophic gastritis whereas the Type 2 GNETs occur in the setting of Zollinger-Ellison Syndrome (ZES) and Type 3 GNETs are not associated with either atrophic gastritis or ZES.^7^ In chronic corpus-involving atrophic gastritis, parietal cells cannot secrete gastric acid which subsequently induces hyperplasia of gastric antral G cells and hypergastrinemia. Gastrin then acts on enterochromaffin-like cells to act as a growth factor and induce cell proliferation that can lead to a Type 1 GNET.^8^ Reassuringly, Type 1 GNETs are rarely metastatic and long-term outcomes are excellent after resection, but vigilance for this malignancy in the setting of chronic atrophic gastritis is critical.^9^
While atrophic gastritis and intestinal metaplasia are well-established features of gastritis, finding a universally accepted definition of the morphological appearance of gastritis has historically proved difficult. Prior to 1990, there was a variety of terminology used to describe the morphological appearance of gastritis, leading to confusion and controversy amongst clinicians and pathologists. In 1990, the ‘Sydney System’ was established using both endoscopic and histologic findings to classify and grade chronic gastritis in a systematic manner. The definition was updated in 1996, leading to the updated Sydney System.
In the updated Sydney System, chronic gastritis is first separated by the presence of absence of atrophy, and if atrophy is present, it is further characterized by the topography of said atrophic gastritis in the stomach.^10^ Topography for the Sydney System biopsies are noted in Figure 1. Often, specific topographic locations of gastritis can point to a specific diagnosis (i.e corpus predominance in lymphocytic gastritis, antral predominance in H. pylori gastritis). The topography of intestinal metaplasia is also important as it can be defined as multifocal or diffuse. Image 1 demonstrates mild chronic gastritis with the presence of multifocal intestinal metaplasia without dysplasia from the gastric antrum.
Once specimens are obtained, there are several variables of interest that are then graded by the pathologist as mild, moderate, or marked (Figure 2). There are also non-graded histologic features including surface epithelial damage, mucous depletion, erosions, lymphoid follicles, foveolar hyperplasia, pseudopyloric metaplasia, and acinar metaplasia, and endocrine cell hyperplasia. The Sydney System also makes a specific comment regarding characterizing subtypes of intestinal metaplasia, as type 1 (complete) intestinal metaplasia has a lower malignant potential than type 3 (incomplete).
While the Sydney System focused predominantly on chronic gastritis, the authors do make a brief comment regarding acute gastritis. Acute gastritis is generally transient, either resolving or progressing to chronic gastritis, so it is rarely seen but the major categories they establish are acute hemorrhagic/erosive gastritis (often related to chemical or irritant injury) and acute Helicobacter gastritis.
Despite the histologic definition and grading established by the updated Sydney System, there remained difficulty in interpreting its clinical significance. To better translate the pathologic information into a score that might convey clinical relevance (i.e cancer risk) an international group of pathologists and gastroenterologists developed the Operative Link on Gastritis Assessment (OLGA).^11^ OLGA is built around a grading and staging concept, where grading refers to the intensity of inflammation and staging refers to the extent of atrophic and metaplastic changes related to cancer risk.
The OLGA grade is determined by assessing the combined severity of mononuclear and granulocytic inflammation in both antral and corpus biopsy samples ranging from 0 (absence of any inflammatory cells) to 4 (very dense infiltrate in all biopsy samples). The combination of corpus and antrum inflammation determines the overall grade (Figure 2). Staging is based on the level of atrophy in the antrum and corpus, where 0 refers to the absence of atrophy and metaplasia while 4 refers to pan-atrophy of all antral and corpus samples (Figure 2).
To validate the OLGA gastritis staging system as a clinical tool for predicting malignancy risk, a prospective cross-sectional study was performed where 439 consecutive patients with dyspepsia underwent a Sydney System biopsy sampling protocol and each patient had their biopsies assessed for gastritis grading and staging per the OLGA protocol.^2^ The findings of the study demonstrated that benign conditions were consistently clustered in stages 0-II while neoplastic lesions were clustered in stages III-IV, supporting the use of the OLGA system in clinical practice as a more straightforward measure of severity of gastritis than the Sydney System.
While the OLGA system provided an easier way for clinicians to interpret cancer risk from pathology reports, high levels of interobserver agreement for atrophic gastritis are notoriously difficult to achieve, making the reliance on atrophy in OLGA problematic.^12^ Because intestinal metaplasia is more easily recognizable in gastric mucosa than atrophic gastritis, Capelle et al. sought to devise a staging system based off intestinal metaplasia called operating link for gastric intestinal metaplasia (OLGIM) to estimate gastric cancer risk.^3^ The structure of the OLGIM system is similar to OLGA, where corpus and antral biopsies are assessed for no, mild, moderate, or severe intestinal metaplasia and the combination of severity between the two locations determines the overall stage. The OLGIM system demonstrated higher rates of inter-observer agreement for intestinal metaplasia compared to atrophic gastritis. When comparing OLGA vs. OLGIM, there were similar staging between groups regardless of use of intestinal metaplasia versus atrophic gastritis and gastric cancer risk was classified equally in the OLGIM and OLGA overall.^3^ The improved reproducibility seen in the OLGIM study may lead to a more consistent gastric cancer risk assessment.
In 2022, the Real-world Gastritis Initiative (RE.GA.IN), a forum of gastritis scholars, met to discuss updates to improve clinical management of patients with gastritis. Their recommendations included sampling at least two corpus and two antral biopsies to diagnose and stage gastritis, with optional incisura biopsies.^13^ They additionally recommend that histology reports contain OLGA/OLGIM stages to determine gastric cancer risk and guide surveillance strategies.
Despite the malignant risk carried by prolonged gastritis, current guidelines remained mixed on the utility of surveillance endoscopy. In 2020 guidelines, the American Gastroenterological Association (AGA) recommended against routine endoscopic surveillance or repeat short-term endoscopy to assist with risk stratification in patients with gastric intestinal metaplasia.^14^ However, both European and United Kingdom guidelines recommend endoscopic surveillance every three years should be offered to patients with extensive atrophic gastritis or gastric intestinal metaplasia.^15, 16^ The European guidelines also note in patients with intestinal metaplasia at a single location, but high-risk risk factors including family history of gastric cancer, incomplete intestinal metaplasia, or Helicobacter pylori gastritis should also consider endoscopic surveillance in three years.^15^
Worldwide, the most common etiology of gastritis remains H. pylori infection, however there are still a variety of other causes of chronic gastritis. A 2015 consensus statement proposed categorizing the etiology of chronic gastritis based on prevalence, dividing it into infectious, autoimmune, and drug-induced.^17^ In the infectious category, other causes include bacteria other than H. pylori, viral gastritis, fungal gastritis, and parasitic gastritis. There are certain etiologies that do not fit specifically into the above three categories but are also included in the consensus statement including lymphocytic, allergic, eosinophilic, as well as gastritis due to other diseases such as sarcoidosis, vasculitis, or Crohn’s disease.
While gastritis has historically been a nebulous term, there has been a recent push to develop standardized protocols for defining and staging histologic findings of gastritis. It is important to note that sampling of both the antral and corpus mucosa is needed for accurate assessment of gastritis in these protocols. Regardless of etiology, standardization in gastritis is driven primarily by the need to convey malignant potential from histopathological findings to actionable clinical information.