Abstract
Gastric hyperplastic polyps (GHP) are frequently found to be benign polyps and have been considered to have a low carcinogenic potential. The characteristics of the hyperplastic polyp-associated gastric cancer (HPAGC) remain unclear. Therefore, we analyzed samples from 102 GHP patients and identified 20 low-grade atypical GHPs (19.6%), 7 high-grade atypical GHPs (6.9%), and 5 intramucosal cancer samples (4.9%). GHP atypia was more common in the elderly and increased with increasing polyp size. In particular, polyps larger than 1 cm were associated with a higher grade and cancer. Furthermore, mucus production decreased with increasing atypia. Although no correlation was found between atypia and Helicobacter pylori infection or intestinal metaplasia, enhanced proliferative ability (Ki-67) did correlate with atypia, as did nuclear 8-hydroxy-2’-deoxyguanosine levels. Interestingly, 4-hydroxynonenal levels in granulation tissue and the area ratio of granulation tissue within polyps also correlated with GHP atypia. In five cases of HPAGC, three cases exhibited caudal type homeobox transcription factor (CDX2)-positive cells and a mixed mucin phenotype, which is considered to be related to H. pylori infection. By contrast, two cases were CDX2 negative, with a gastric mucin phenotype, and H. pylori infection was not observed in the tumor or the surrounding mucosa. In these cases, a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation (V600E) was detected. All cancer samples showed high stemness and p53 protein accumulation, but no KRAS mutations. The molecular and phenotypic characteristics of the cases characterized by BRAF mutations may represent a novel subtype of HPAGC, reflecting a conserved pathway to oncogenesis that does not involve H. pylori infection. These findings are worthy of further investigation in a large-scale study with a substantial cohort of HPAGC patients to establish their clinical significance.
Highlights
Gastric cancer is currently the third most common cause of cancer-related death inJapan [1]
We classified Gastric hyperplastic polyps (GHP) atypia into four categories: non-atypical GHP with no nuclear and no structural atypia with abundant mucus production; low-grade atypia with mild to moderate nuclear swelling; high-grade atypia with moderate to prominent nuclear swelling, pseudostratified nuclei, and decreased periodic acid–Schiff (PAS)-positive mucus production; and hyperplastic polypassociated gastric cancer (HPAGC) with the cellular characteristics of high-grade atypia as well as structural atypia and/or invasion (Figure 1). Using this categorization process to sort the samples from 102 GHP patients, we identified 20 GHP samples as low-grade atypia, 7 GHP samples as high-grade atypia, and
Using this categorization process to sort the samples from 102 GHP patients, we identified 20 GHP samples as low-grade atypia, 7 GHP samples as high-grade atypia, and 5 GHP samples as HPAGC (Table 1)
Summary
Gastric cancer is currently the third most common cause of cancer-related death inJapan [1]. We showed that the activation of oxidative stress and v-akt murine thymoma viral oncogene homolog (AKT) increased substantially in each of the following categories of chronic gastritis: chronic gastritis without H. pylori, chronic active gastritis with H. pylori, chronic metaplastic gastritis without H. pylori, and chronic gastritis with atypia without H. pylori [4]. This is due to the shortening of telomeres and activation of telomerase reverse transcriptase, which are associated with repeated mucosal regeneration due to chronic inflammation [5] and are thought to lead to hyperplasia of gastric mucosal stem cells [6,7]. GHPs are thought to occur during the repair of damaged mucosa [9]
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