Precursor‐derived versus <i>de‐novo</i> carcinogenesis depends on lineage‐specific mucin phenotypes of intramucosal gland‐forming gastric neoplasms

Nishimura, Rie; Mukaisho, Ken‐ichi; Yamamoto, Hiroto; Sonoda, Ayano; Andoh, Akira; Fujiyama, Yoshihide; Hattori, Takanori; Sugihara, Hiroyuki

doi:10.1111/his.12208

Cited by 8 publications

(15 citation statements)

References 19 publications

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“…At variance, within cases immunophenotyped as intestinal, low-grade dysplasia was the most frequent (86.4 %; p = 0.001). These findings are in keeping with those recently reported by Nishimura et al [14], but differ from the results reported by Abraham et al [20]; the latter showed that intestinal-type adenomas were more likely than gastric-type adenomas to display high-grade dysplasia and adenocarcinoma in the polyps. A major difference from this study is that although the series studied by Abraham et al [20] is composed of polypoid adenomas, our series is constituted by nonpolypoid dysplasia, not including polypoid/protruded lesions.…”

Section: Discussionsupporting

confidence: 83%

“…However, evidence from the literature points to the possible existence of alternative pathways in which intestinal metaplasia may not be involved. Evidence stems mainly from the study of tiny early GCs arising in nonmetaplastic mucosa, as described by Japanese authors [14,15] as well as the studies of the expression of markers of gastric differentiation in dysplasia and gastric adenocarcinoma [7, 10, 16, 17]. The latter demonstrate that both types of lesions may express, predominantly or exclusively, markers of gastric differentiation, raising the possibility of an origin in native gastric mucosa, rather than in intestinal metaplastic lesions.…”

Section: Discussionmentioning

confidence: 99%

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Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness

et al. 2014

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Background Gastric dysplasia is classified as adenomatous/type I (intestinal phenotype) and foveolar or pyloric/ type II (gastric phenotype) according to morphological (architectural and cytological) features. The immunophenotypic classification of dysplasia, based on the expression of the mucins, CD10 and CDX2, recognizes the following immunophenotypes: intestinal (MUC2, CD10, and CDX2); gastric (MUC5AC and/or MUC6, absence of CD10, and absent or low expression of CDX2); hybrid (gastric and intestinal markers); and null.Methods Sixty-six cases of nonpolypoid epithelial dysplasia of the stomach were classified according to morphological features (histotype and grade) and immunophenotype. Immunohistochemical staining was performed with antibodies against MUC2, MUC5AC, MUC6, CD10, CDX2, chromogranin, synaptophysin, Ki-67, and TP53. HER2 alterations were analyzed by immunohistochemistry and silver-enhanced in situ hybridization.Results By conventional histology, dysplasia was classified as adenomatous/intestinal (n = 42; 64 %) and foveolar or pyloric/gastric (n = 24; 36 %) and graded as low grade (n = 37; 56 %) or high grade (n = 29; 44 %). Immunophenotypic classification showed intestinal (n = 22; 33.3 %), gastric (n = 25; 37.9 %), hybrid (n = 17; 25.8 %), or null (n = 2; 3.0 %) phenotypes. In 20 cases a coexistent intramucosal carcinoma was identified. The intestinal immunophenotype was shown to be significantly associated with low-grade dysplasia (p = 0.001), high expression of CDX2 (p = 0.015), TP53 (p = 0.034), synaptophysin (p = 0.003), and chromogranin (p \ 0.0001); the gastric immunophenotype was significantly associated with high-grade dysplasia (p = 0.001), high Ki-67 proliferative index (p = 0.05), and coexistence of intramucosal carcinoma (p = 0.013). HER2 amplification was observed in 3 cases, typed as gastric or hybrid. Conclusions Epithelial nonpolypoid dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness and may represent the putative precursor lesion in a pathway of gastric carcinogenesis originated de novo from the native gastric mucosa, leading to gastric-type adenocarcinoma.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness

et al. 2014

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“…It means that intestinal metaplasia is not always a ‘precancerous’ lesion but a ‘paracancerous’ lesion. In our recent report, we found that early intramucosal gastric cancer lesions possessed gastric mucous phenotypes and that there is a proliferative zone with a polarity of differentiation in mucous phenotypes that is similar to the intrinsic gastric glands . Thus, it does not appear that intestinal metaplasia is a major oncogenic pathway for gastric cancer.…”

Section: Is It True That ‘Only Intestinal Metaplasia Results In Cancer’?mentioning

confidence: 95%

Barretts's carcinogenesis

Mukaisho

Kanai

Kushima

et al. 2019

Pathology International

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Barrett's esophagus is considered a precancerous lesion of esophageal adenocarcinoma (EAC). Long‐segment Barrett's esophagus, which is generally associated with intestinal metaplasia, has a higher rate of carcinogenesis than short‐segment Barrett's esophagus, which is mainly composed of cardiac‐type mucosa. However, a large number of cases reportedly develop EAC from the cardiac‐type mucosa which has the potential to involve intestinal phenotypes. There is no consensus regarding whether the definition of Barrett's epithelium should include intestinal metaplasia. Basic researches using rodent models have provided information regarding the origins of Barrett's epithelium. Nevertheless, it remains unclear whether differentiated gastric columnar epithelium or stratified esophageal squamous epithelium undergo transdifferentiation into the intestinal‐type columnar epithelium, transcommittment into the columnar epithelium, or whether the other pathways exist. Reflux of duodenal fluid including bile acids into the stomach may occur when an individual lies down after eating, which could cause the digestive juices to collect in the fornix of the stomach. N‐nitroso‐bile acids are produced with nitrites that are secreted from the salivary glands, and bile acids can drive expression of pro‐inflammatory cytokines via EGFR or the NF‐κB pathway. These steps may contribute significantly to carcinogenesis.

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“…However, some EGCs do not match this histogenesis theory in clinical settings; some differentiatedtype carcinomas have been found to occur from the ordinary gastric gland mucosa without IM, in which it is especially difficult to diagnose invasion depth of the carcinoma [4][5][6][7][8][9] . Endoscopists predict submucosal invasion of EGC from the macroscopic findings of focal thickness and ulceration in the cancer lesion [14][15] .…”

Section: Discussionmentioning

confidence: 99%

“…Although it is generally accepted that most EGCs conform to Nakamura's histogenesis theory, some pathologists have reported that differentiated-type carcinoma is occasionally derived from the ordinary gastric mucosa. Further, they believe that this type of lesion can be classified as gastric-type based on the mucin phenotypic expression and specific biological behavior [4][5][6][7] . By contrast, among the clinical endoscopic field, it is still difficult to assess the lateral extent and invasion depth of differentiated-type adenocarcinoma derived from the ordinary gastric mucosa before endoscopic treatment [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Mucin Phenotypic Expression and Submucosal Invasion of Gastric Differentiated-type Adenocarcinoma with Minimal Intestinal Metaplasia

Nakashima¹,

Yamasaki²,

Owari³

et al. 2016

Journal of Gastroenterology and Hepatology Research

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9.6% of all EGCs. Among those with a gastric phenotype, the rate of submucosal invasion was 62.5%, which was significantly higher than that in the incomplete intestinal-type cases (12.5%). CONCLUSION: Our results indicated that information regarding the mucin phenotypic expression is beneficial for predicting submucosal invasion of differentiated-type carcinoma surrounded by minimal IM. INTRODUCTIONGastric carcinoma is categorized into a number of diverse histological types, but there have been attempts to simplify the classification into just two groups based on the presence or absence of gland formation. Western countries have adopted Lauren's categorization system whereby gastric carcinomas are divided into diffuse-type and intestinal-type [1] , while Nakamura's classification into differentiated and undifferentiated-types has been mainly used in Japan [2] . The latter system divides gastric carcinomas into two groups based on not only gland formation, but also histogenesis, i.e., differentiated-type adenocarcinoma arises from gastric mucosa with intestinal metaplasia (IM), while undifferentiated-type adenocarcinoma is derived from the ordinary gastric mucosa without IM. ABSTRACT AIM: The gastric differentiated-type adenocarcinoma, which basically arises from intestinal metaplasia (IM), is occasionally derived from the ordinary gastric mucosa without intestinal metaplasia. However, in the clinical endoscopic field, it is still difficult to diagnose the invasion depth of differentiated-type adenocarcinoma surrounded by the ordinary gastric mucosa. The aim of our research was to clarify the prediction method of submucosal carcinoma invasion of these lesions. MATERIALS AND METHODS:The study population consisted of 282 early gastric cancer (EGC) lesions. The degree of histological IM in the background mucosa was classified according to The Updated Sydney System, moreover cases with normal and mild grades of IM were considered to have minimal IM. Mucin immunohistochemical staining was performed on 27 EGCs of the differentiated-type with background mucosa minimal IM, followed by classification into four mucin-phenotypes according to the expression of MUC5AC, MUC6, MUC2, and CD10.

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Precursor‐derived versus de‐novo carcinogenesis depends on lineage‐specific mucin phenotypes of intramucosal gland‐forming gastric neoplasms

Abstract: Intramucosal adenocarcinomas of the gastric lineage may often arise de novo, develop in the proper gastric mucosa, and are partially derived from non-invasive high-grade neoplasms.

Cited by 8 publications

References 19 publications

Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness

Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness

Barretts's carcinogenesis

Mucin Phenotypic Expression and Submucosal Invasion of Gastric Differentiated-type Adenocarcinoma with Minimal Intestinal Metaplasia

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