Front Oncol. 2023 Oct 24;13:1176673. doi: 10.3389/fonc.2023.1176673.
Gastric cancer의 prevalence는 지난 10년 동안 점차 감소하고 있으나, 여전히 높은 mortality와 사망률을 보이고 있습니다. Cancer의 발생은 유전적인 요인 보다는 어린 시절 carcinogenic agent의 노출에 의한 경우가 주요 원인으로, 위염을 일으키는 H. pylori 감염이 중요한 원인이라고 할 수 있습니다. 이번 review에서는 gastric cancer의 classification, etiology, pathogenesis를 살펴 보겠습니다. 특히, 위암에서 ECL cell인 neuroendocrine cells와 gastrin의 역할에 대해서 살펴 보도록 하겠습니다.
Classification of gastric carcinomas, macroscopic and microscopic
Diffuse type gastric cancer (Borrmann type IV, Linitis platisca)는 Lauren’s criteria에 따라 glandular growth pattern을 갖는 intestinal type 과 구분된 조직학적 특징을 갖으며, exocrine cell에서 만들어지는 mucin에 대한 PAS 염색 시 양성을 띠기 때문에 adenocarcinoma로 분류하고 있습니다. 하지만, PAS는 mucin 및 glycoprotein에도 친화성을 가지고 있으며, immunochemistry나 in situ hybridization으로 검사를 해보면 diffuse type gastric cancer cells에서 mucin expression을 찾을 수 없으므로 adenocarcinoma의 classification하는 데는 논쟁의 소지가 있습니다. 반면에, general neuroendocrine markers (chromogranin A, synaptophysin, neuron-specific enolase)와 ECL cell marker histidine decarboxylase (HDC)의 expression은 gastric cancer 의 immunohistochemistry에서 확인되고 있고, 특히 diffuse type에서도 관찰되고 있습니다. 특히, Chromogranin A는 immuno-electron microscopy를 이용하여 diffuse gastric carcinoma의 cancer cells 내 granules에서 관찰할 수 있으며, in situ hybridization을 이용하여 gastric carcinoma cell에서 관찰됩니다.
최근 몇 십년간 intestinal type cancer는 감소하고 있으나 diffuse type의 cancer는 변화가 없으며, 이는 오히려 증가하는 추세로 생각할 수 있습니다. 또한, diffuse type cancer에 ECL cells에서 기인하는 neuroendocrine carcinoma도 포함시킬 수 있습니다.
Gastric cancer는 진단 당시의 연령에 따라 conventional 과 early-onset gastric cancer로 분류해 볼 수도 있는데, 이는 발생 연령에 따른 임상적 차이가 있기 때문입니다.
The etiology/pathogenesis of gastric cancers
H. pylori는 gastritis와 gastric cancer를 일으키는 원인으로 잘 알려져 있습니다 (type 1 carcinogen). 그리고 H. pylori 감염이 되어 진행되는 oxyntic atrophy는 gastric cancer의 선행 병변이며, hypoacidity와 gastric cancer 사이의 연관성도 잘 알려져 있습니다. H. pylori의 virulence factors인 cag A와 vag A 여부에 대한 bacterium strains의 차이와 gastric cancer 연관성에 focus가 되어 연구 되었으나, 2000년대 초 virulence factors가 과거에 생각했던 것 만큼 중요하지 않기 때문에, cagA와 vag A 유무에 관계없이 H. pylori는 gastric cancer를 일으키는 원인입니다. 하지만, H. pylori의 strains에 따라 carcinogenic potential은 차이가 있을 수 있습니다.
H. pylori 감염 초기에는 dyspepsia, nausea 등의 증상이 있을 수 있고, antrum에 국한되며 urase activity는 gastrin 분비를 촉진시켜 acid 분비가 증가하므로, duodenal ulcer 등의 발생 가능성이 높아집니다. 또한, dupA 와 같은 duodenal ulcer와 연관된 gene의 경우 gastric cancer risk는 낮은 것으로 알려져 있습니다.
H. pylori eradication 이후에도 gastric cancer의 risk를 완전히 제거하지 못합니다.
The pathogenesis of H. pylori and autoimmune gastritis in gastric cancer via hypergastrinemia
Gastrin and the target cell, the enterochromaffin-like (ECL) cell
Figure 1. Gastrin and the ECL cell are central in gastric cancers of both diffuse and intestinal types.
TABLE 1 Gastrin has for decades been known to be an important trophic hormone for the oxyntic mucosa. Its role in gastric carcinogenesis has been underestimated because:.
H. pylori is the main cause of gastric cancer. EBV-associated gastric cancers can be diagnosed by in situ hybridization, and in a large surgical study of gastric cancers 6.1% were positive.
In a recent study conducted in China, salted fish, in contrast to processed meat, did not increase the risk of gastric cancer. Excluding food and water contaminated with H. pylori, we will conclude that the intake of different types of food may have only a slight effect on gastric carcinogenesis.
In a large meta-analysis of epidemiological studies, there was an increased risk in smokers, both present and previous, compared with non-smokers. Although statistically significant differences were found, the odds ratios were rather low. Since engagement in tobacco smoking is rapidly declining, however, this factor will be of less importance in the future.
The case of this Spanish family demonstrates without doubt that long-term hypoacidity will lead to cancer and thus the risk of profound acid inhibition (Fossmark R, Calvete O, Mjones P, Benitez J, Waldum HL. ECL-cell carcinoids and carcinoma in patients homozygous for an inactivating mutation in the gastric H(+) K(+) ATPase alpha subunit. Apmis (2016) 124:561–6. doi: 10.1111/apm.12546).
Hereditary gastric cancer of the diffuse type due to a missense mutation of the CDH1 gene coding for E-cadherin is a more prevalent type of genetic gastric cancer. It should be mentioned that E-cadherin expression in ECL cells was not found by immunocyte/histochemistry, indicating that this cell type could be prone to invasion and metastasis.
Prophylaxis and therapy
TABLE 2 Rational prophylaxis of gastric cancer in individuals with H. pylori infection or with autoimmune gastritis.
The etiology and pathogenesis of gastric cancer are well known, and better known than for most other cancers. The central role of H. pylori (a bacterium) in gastric cancer is unique, although its effect (via inducing oxyntic atrophy leading to hypoacidity and hypergastrinemia) is indirect. Gastric carcinomas were classified in accordance with Lauren’s criteria based on morphology as adenocarcinomas of intestinal and diffuse types depending on whether or not the presence of glandular structures was detected. This classification represents an important difference since the two types do not transform into the other, and the decline in prevalence seen in the last few decades is selective for the intestinal type. The diffuse type was initially classified among adenocarcinomas because PAS positivity was thought to represent mucin and thus exocrine cells. However, PAS has an affinity for glycoproteins in general. Many of the diffuse types express neuroendocrine and, more specifically, ECL cell markers, suggesting that these cancers develop from ECL cells, which are the target cells of gastrin.
Hypergastrinemia due to atrophic oxyntic gastritis also predisposes affected individuals to gastric cancer of the intestinal type, presumably originating from stem cells stimulated directly or indirectly (Reg protein from ECL cells) by gastrin. Moreover, all conditions resulting in gastric hypoacidity, including autoimmune gastritis, H. pylori gastritis, and profound acid inhibition due to PPIs will necessarily predispose affected individuals to gastric cancer. Since carcinogenesis most often is a slow process, a latency of decades must be expected. The central role of gastrin in gastric carcinogenesis provides an opportunity to prevent many gastric cancers. This may be achieved by the eradication of H. pylori before the occurrence of oxyntic atrophy, by avoiding the long-term use of drugs with profound inhibition of gastric acid secretion and by using gastrin antagonists when they become available, in those with autoimmune gastritis and in those with oxyntic atrophy due to previous H. pylori infection. Taking these steps will hopefully mean that gastric cancer becomes a rare disease.
The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid–Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and in situ hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, Helicobacter pylori, is thought to be its main cause. H. pylori predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single H. pylori factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to H. pylori, autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by H. pylori eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term H. pylori infection and those with autoimmune gastritis.
KEYWORDS: gastric cancer, types of gastric cancer, neuroendocrine carcinoma, Helicobacter pylori, gastrin
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