Gastric cancer, despite the observed declining trends in incidence in many countries, remains a significant diagnostic and therapeutic challenge. In 2020, it was the fourth most common cause of cancer-related deaths worldwide (1). In Poland, this cancer is the fifth leading cause of cancer-related deaths in men and the eighth in women (2). This malignancy occurs almost twice as often in men as in women. The highest incidence rates in both sexes are observed in East Asia (including Japan and Mongolia), while in men, high rates are also reported in Western Asia (notably in Turkmenistan and Iran) (3). In the United States, the 5-year survival rate for gastric cancer is 31% (4).

Early diagnosis, being one of the most important prognostic factors impacting the overall survival, is hindered by the initially asymptomatic course of the disease and the nonspecific nature of symptoms in its early stages (5, 6). The most common symptoms generally include epigastric pain, a feeling of nausea, and fatigue, which, in most cases, tend to appear only when the cancer is already in an advanced stage (7). As a result, gastric cancer is still diagnosed frequently at a late stage of the disease, when palliative care becomes the only therapeutic option. In patients diagnosed earlier, combination of surgery and chemotherapy still belongs to the mainstay of treatment. In rare cases of disease limited to the superficial layers of the gastric wall without systemic involvement, endoscopic submucosal dissection (ESD) can serve as a single, curative procedure (6).

Although genetic predisposition is crucial in gastric cancer pathogenesis, the significant variation in the incidence of the disease across different countries and regions of the world indicates a crucial etiological influence of environmental factors. This was demonstrated, for example, in a study of Japanese populations who emigrated to Hawaii. The incidence of gastric cancer in the first generation of emigrants was lower than in those who remained in Japan. In each subsequent generation, the incidence continued to decline, although it remained higher than in the native Hawaiian population (8).

Modifiable environmental risk factors for gastric cancer include Helicobacter pylori (H. pylori) infection, low socioeconomic status, alcohol consumption, smoking, and an unhealthy diet (5). These factors particularly affect the intestinal type of gastric cancer according to the Lauren’s classification (9, 10). The specific mechanisms leading to the development of gastric cancer are not well understood. However, it appears that chronic inflammation resulting from the factors mentioned above may play a key role, leading to atrophic gastritis and intestinal metaplasia (11). This sequence, which may lead to dysplasia and, subsequently, the development of intestinal type of gastric cancer, is also known as the Correa’s cascade (10, 12). The pathogenesis of a diffuse type of gastric cancer is known to a significantly lesser extent.

Environmental factors, crucial in the pathogenesis of gastric cancer, change over the years and are subject to modification, which can significantly impact the incidence of gastric cancer and the biology and histology of the disease. However, there are still few studies exploring this issue. Considering the paucity of data in this topic, we decided to conduct a comparative analysis of the histological and biological characteristics of gastric cancers, including H. pylori infection status and Ki-67 proliferation index, across two distinct time periods in Western Poland. This region is part of a country which has experienced one of the most dynamic, on a global scale, radical environ-mental, political, civilizational, and economic changes over the past decades (13–15).

The final study group consisted of 92 patients who underwent surgical treatment due to gastric cancer in two 5-year time periods: 1998-2002 (n=47) and 2016-2020 (n=45). The subgroups were comparable in terms of age and gender (Table 3), with a significant predominance of male patients in both timespans (1998-2002: 31/47– 66% vs. 16/47 – 34%, p=0.03; 2016-2020: 33/45 – 73% vs. 12/45 – 27%, p=0.005).

Our study showed that despite significant changes in many environmental factors in the last two decades, no differences were noted over two different time periods (1998–2002 vs 2016-2020) in terms of the histopathological characteristics of gastric cancers in the population studied. Considering the crucial prognostic role of early detection of gastric cancer, no increase in the percentages of early gastric cancer subtypes and no differences in tumor staging at the time of surgery as assessed by the pTNM classification among contemporarily diagnosed patients seem to be the most disappointing results from our study. These results are in contrast with data presented by Popiela et al. They compared two groups of operated patients from 1977–1999 and 1989-1999, showing a statistically significant increase in resected early-stage gastric cancers and a decrease in the number of patients operated with the most advanced disease (31). On the other hand, Borsh et al. analyzed 1161 patients operated on in Sweden due to gastric cancer from 1974-1991. Similarly to our study, they did not find a statistically significant differences in the detectability of early disease subtype throughout time (32). Conversely, Japan shows one of the highest diagnostic rates for early gastric cancer, reaching 50% compared to approximately 15% in Europe and 20% in the United States (10, 33, 34).

These differences in the detection rates of non-advanced gastric cancers can result, among others, from different strategies regarding screening programs or the quality of upper gastrointestinal endoscopy in different countries (35, 36). That is why, considering the data presented in our study and the fact that gastric cancer still belongs to the group of malignancies with the worst prognosis, it seems essential to promote strategies aimed at increasing the detection rates of early type of the disease. Common implementation of the recommendations given by the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG), and European Society of Pathology (ESP) (37, 38) on endoscopic screening for gastric cancer among patients with severe atrophic gastritis and/or extensive intestinal metaplasia can be one of the proposed options. Another strategy would be to promote constant education in the quality of upper gastrointestinal endoscopy.

The lack of observed changes in the histological characteristics of the tumor (histological type, according to the WHO 2019 classification, Lauren’s classification, and histological grading) may be related to the influence of genetic and environmental factors. Genetic factors are not subject to modification, unlike the environment. Environmental factors are an essential part of the pathogenetic background of stomach cancer, as evidenced by noticeable differences in the incidence rates in various countries and regions worldwide (3). The last decades have represented two opposing trends regarding the environment and the lifestyle of populations in developed countries. On the one hand, there is a progression of air and water pollution, soil contamination, as well as the consumption of highly processed food rich in preservatives, and an obesity epidemic (10, 39). On the other hand, many countries have undertaken a series of pro-ecological initiatives, there has been a gradual improvement in people’s awareness of environmental protection (40), and there have been improvements in food storage conditions. There is a promotion of dietary habits that limit salt consumption and animal products and a dynamic popularization of Mediterranean or vegetarian diets (39, 41). The phenomena mentioned above also occur in the Polish population, where the last decades have been a period of exceptional, on a global scale, radical political, civilizational, and economic changes (42). Despite the relatively short period between the compared groups of patients in this study, they represent two different perspectives - the initial period of transformation (late 1990s) and the contemporary perspective, which seems sufficient to capture hypothetical trends regarding the differences in the characteristics of stomach cancers. It is worth noting that the issue of environmental influence is very complex and poorly understood. Analyzing the work of Yin and colleagues, who reviewed studies on the impact of environmental factors relevant to stomach cancer, one can conclude that environmental factors may have a slightly different relationship with the occurrence and prognosis of stomach cancer depending on the region under consideration (43). Moreover, these factors sometimes act synergistically and, in other cases, additively. It is, therefore, difficult to precisely identify which environmental elements are crucial. Nevertheless, the association with selected features characterizing the problem of stomach cancer is evident. According to the Lauren’s classification, there has also been a global decrease in the incidence of intestinal-type stomach cancers, which is associated, among other factors, with lifestyle, diet, and environmental factors (9, 10, 44). However, this trend was not observed in the current analysis.

In our study, immunohistochemical comparison analysis of the specimens be-tween the two predefined groups was also performed. This was feasible since the compared patient groups did not differ in general (age, gender) and histological characteristics. We found that Ki-67 proliferation index reached significantly higher values among patients operated on between 2016 and 2020 than among those under-going surgery between 1998 and 2002. Ki-67 is a protein engaged in all cell cycle phases except for the G0 phase, so a high proliferation index may indicate a more aggressive tumor growth (45). Regarding gastric cancer, we have evidence confirming this hypothesis. For example, Ko et al. evaluated the prognostic value of Ki-67 protein ex-pression in a group of 320 patients, finding that it has negative prognostic significance, especially for early and well-differentiated gastric cancers (46).

A statistically significant higher mean Ki-67 proliferation index was found among intestinal types of tumors according to the Lauren’s classification among patients from both timeframes. This observation may be somewhat surprising because, as mentioned above, a higher proliferation index, measured by Ki-67 expression, is associated with a worse prognosis, similar to the diagnosis of diffuse cancer compared to intestinal cancer. However, in accordance with this result, a statistically significantly higher mean Ki-67 proliferation index was seen in the group of patients with E-cadherin expression in tumor cells. This adhesive protein is closely associated with the intestinal type of gastric cancer, according to Lauren’s classification (47). Additionally, similar data was published by Tokuyasu et al. (48) in a more detailed analysis, Ko et al. also showed significantly higher Ki-67 expression in intestinal-type gastric cancers and hypothesized that Ki-67 might have different prognostic values in individual subtypes of gastric cancer being particularly useful in well-differentiated tumors (46). Therefore, the worse prognosis of poorly differentiated and diffuse-type cancers is determined by more complex and less obvious mechanisms, which are not reflected solely by Ki-67 expression, as is in the case of intestinal-type tumors.

Ki-67 was correlated with both p53 expression and MSI in the whole study group, nicely reflecting the current knowledge on their prognostic role in gastric cancer (49, 50). Moreover, a positive relationship was observed between the number of vessels in the tumor stroma and the Ki-67 index, but only in the group of patients operated on between 2016 and 2020. In the earlier surgical cohort, no trend approaching statistical significance was observed. Therefore, it can be assumed that the degree of proliferation of cancer cells in tumors diagnosed recently depends at least partly on tumor vascularity. Similar relationships are known for other types of gastrointestinal malignancies (51). However, the use of angiogenesis inhibitors and anti-proliferative agents in chemotherapy regimens for gastric cancer has not shown consistent efficacy, and their clinical relevance remains uncertain (52).

In this study, it was demonstrated that H. pylori -positive gastric cancers diagnosed only between 2016 and 2020 revealed a significantly higher tumor proliferation index Ki-67. Gucin et al. also found a statistically significant increase in the Ki-67 proliferation index in patients with gastric cancer infected with H. pylori (53). Similarly, Shiotani et al. showed that H. pylori infection increases the Ki-67 proliferation index and the apoptosis of gastric cells, which leads to intestinal metaplasia and thus to gastric cancer (54). This interesting relationship, which was not documented in our cohorts among cancers from the earlier period, may be related to the differences in H. pylori’s virulence, modified by environmental factors changing over time, which was well documented in experimental models (55).

In the above-mentioned context, the lack of a difference in the percentage of H. pylori-infected patients with gastric cancer between the two study periods may seem especially alarming considering that knowledge and recommendations regarding H. pylori eradication have significantly changed during this time. In 1997, worldwide guidelines for eradicating H. pylori as a key pathogenic factor in gastric cancer were introduced for the first time (56). These guidelines initially suggested treating infection only in selected cases, and awareness among physicians regarding the necessity and principles of therapy gradually and slowly increased. In contrast, 2016–2020 represents the period of the Maastricht V/Florence recommendations, according to which H. pylori eradication should be implemented in every diagnosed patient (57). Consequently, the percentage of H. pylori infections among the gastric cancers studied should de-crease, which was not the case. Therefore, it seems essential to undertake educational activities to further disseminate knowledge among healthcare workers regarding the adherence to currently applicable recommendations based on strong scientific evidence by international expert groups.

Currently, in many countries, including Poland, there is no population-based screening program for gastric cancer or H. pylori infection. There is ongoing debate and controversy regarding how such screening should be implemented—whether through endoscopic examinations or non-invasive H. pylori testing. Taking into ac-count the results and conclusions of our study, one could consider initiating screening with H. pylori testing, especially given its established role in gastric carcinogenesis. It should also be noted that endoscopy, although accurate, is expensive and technically demanding (58). Therefore, the inclusion of a gastric cancer screening strategy may be worth further consideration.

Our study has several limitations. Firstly, the study is retrospective in nature. Considering the significance of the problem and the results obtained, it would be interesting to conduct a long-term multicenter prospective study to verify the hypotheses presented in our analysis. Secondly, a limitation of our study is its single-center design. Although the research was conducted at the Pathomorphological Reference University Centre in Poznan — the largest facility of its kind in one of the most populous regions of Poland — the results may not be fully generalizable to the entire Polish population. It is also important to note that this study is primarily morphological and histopathological in nature, and was not designed to include clinical outcome correlations. Another limitation is the potential difference in patient selection between cohorts due to the increasing use of neoadjuvant therapy in more recent years. Although patients who received such treatment were excluded from the study, and tumor characteristics remained comparable between groups. Another limitations of our study is the selection of biomarkers. We focused on a specific panel including: CD31, Bcl-2, p53, Ki-67, CD10, E-cadherin, Epstein-Barr virus and H. pylori antigens, PMS2, and MSH2. We are aware, however, that there are additional valuable biomarkers, such as PD-L1 and HER2, which could have provided further insights and their evaluation represents an interesting direction for future research. In this study, MSI assessment was performed using PMS2 and MSH2 immunohistochemical evaluation. Although this approach provides a reliable overview of mismatch repair status, it does not include MLH1 and MSH6, which could offer additional complementary information. Other limitation is the lack of knowledge regarding a long-term follow-up of the patients included, which could allow us to assess the possible clinical implications of the study findings.

In conclusion, despite ongoing dynamic changes in environmental and socioeconomical status in Western Poland, we found no significant differences in histopathological characteristics of gastric cancers coming from two distant timeframes. On molecular level, however, cancer tissues obtained contemporarily seem to demonstrate more proliferative potential. From clinical point of view, no decrease in the percentages of non-advanced gastric cancers qualified for surgery and no improvement in the frequency of H. pylori-positive cases represent the most alarming findings. Although these observations should be further confirmed in larger, prospective cohorts, efforts to improve the quality of care with regard to early detection of gastric cancer and proper management of possible oncogenic factors should be implemented without delay.