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Poor nutrition and weight loss are important factors contributing to poor quality of life (QOL) after gastrectomy in patients with gastric cancer. Ghrelin is a hormone produced by the stomach that, plays a role in appetite increase and fat storage. The present study aims to clarify the location of ghrelin mRNA in the stomach, changes in blood ghrelin concentrations after gastrectomy and whether or not they are associated with the reconstruction method in patients with gastric cancer. We collected seven normal mucosa samples from different parts of six totally resected stomachs with gastric cancer. We extracted RNA from the normal mucosa, synthesized cDNA from total RNA (1 μg), and then quantified ghrelin mRNA using quantitative real-time polymerase chain reaction (Q-PCR). Ghrelin blood concentrations were measured using enzyme-linked immunosorbent assay (ELISA) kits in 74 patients with gastric cancer (total gastrectomy (TG), n=23; distal gastrectomy (DG), n=30; proximal gastrectomy (PG), n=11; pylorus preserving gastrectomy (PPG), n=10). In order, the ghrelin gene was expressed most frequently in the gastric body, followed by the fornix, cardia, antrum and pylorus ring. Blood ghrelin concentrations after surgery similarly changed in all groups. The average blood ghrelin concentrations were significantly higher in the DG and PPG groups than in the TG group on postoperative days (POD) 1, 7, 30, 90 and 180. However, blood ghrelin concentrations did not significantly differ between the DG and TG groups on POD 270 and 360. Cells that produce ghrelin are supposed to be located mostly in the fundic gland of the stomach. We speculate that the production of ghrelin from other organs increases from around nine months after total gastrectomy. Therefore, evaluating the nutritional status and the weight of patients at nine months after total gastrectomy is important to help these patients improve their QOL.

Background Rapidly proliferating stomach stem cells have been predicted to be located at the isthmus of both corpus and antrum. We recently identified such stem cells by using 270 bp Runx1 enhancer element, eR1 (Gastroenterol, 2017). In addition, eR1 also marked small number of fully differentiated chief cells in the corpus. We investigated whether chief cells have stem cell activity and can be an origin of gastric cancer, particularly because there are disagreements among the researchers. Methods We generated knock-in mice of pepsinogen C-CreERT2 and crossed them with Rosa26-EYFP mice or pepsinogen A-CreERT2 and crossed them with Rosa26-tdTomato mice for lineage tracing. PGC-CreERT2 mice were also crossed with K-rasG12D/+, Trp53flox/flox and Apcflox/floxmice for carcinogenesis model. Those mice were injected with Tamoxifen 2 mg alternate days for 6 timesto activate Cre recombinase in the chief cells. Results By activating Cre recombinase, we showed that relatively small number of chief cells was retro-differentiated into neck, parietal, pit and enteroendocrinecells suggesting that chief cells underwent differentiation in exact reverse order to make a complete gland unit. When K-rasG12Dwas activated by pepsinogen C-CreERT2, induction of metaplasia was observed. Addition of p53 knockout with K-rasG12Dinto chief cells showed increasing number of glands with metaplasia. Furthermore, addition of APC knockout combination with K-rasG12Dand p53f/fshowed invasive intestinal type gastric cancer in the corpus. These results suggest that at least small subfraction of chief cell have stem cell activity and potential to give rise to gastric cancer. Recently, new entity of gastric adenocarcinoma has been proposed which called Gastric adenocarcinoma of fundic gland type (chief cell predominant type). We might have showed those type of gastric carcinogenesis. Conclusions Chief cell in stomach have stem cell activity and potential to develop gastric cancer. Legal entity responsible for the study The authors. Funding Singapore Gastric Cancer Consortium. Disclosure All authors have declared no conflicts of interest.

Purpose Gastric adenocarcinoma of the fundic gland type (chief cell predominant type) (GA-FG-CCP) was first reported as a rare adenocarcinoma found in the normal fundic mucosa. Recent studies have proposed the possibility that GA-FG-CCPs were also generated in the atrophic mucosa after Helicobacter pylori (HP) eradication therapy. However, little is known on the endoscopic findings of GA-FG-CCP generated in the atrophic mucosa due to its extreme rarity. Materials and methods A total of 8 patients who underwent endoscopic submucosal resection and were diagnosed with GA-FG-CCP generated in the HP-uninfected mucosa (4 cases, HP-uninfected group) or HP-eradicated atrophic mucosa (4 cases, HP-eradicated group) were retrospectively analyzed, and their endoscopic findings, including magnifying endoscopy with narrow band imaging (M-NBI), and pathological features were compared. Results While GA-FG-CCPs in the 2 groups displayed similar macroscopic appearance, M-NBI demonstrated that characteristic microvessels (tapered microvessels like withered branches) were specifically identified in the HP-eradicated group. Pathological investigation revealed that a decreasing number of fundic glands and thinned foveolar epithelium covering tumor ducts were thought to lower the thickness of the covering layer over tumor ducts in the HP-eradicated group. Moreover, dilation of vessels just under the surface of the lesions contributed to the visualization of microvessels by M-NBI. Conclusions The change in background mucosa due to HP infection influenced the thickness of the covering layer over the tumor ducts and M-NBI finding of GA-FG-CCP.

Gastric adenocarcinoma of the fundic gland (chief cell predominant type, GA-FG-CCP) was recently proposed as a new, rare variant of gastric adenocarcinoma. The aim of the current study was to evaluate the endoscopic features of GA-FG-CCP. A total of 10 GA-FG-CCPs were included and evaluated retrospectively. The endoscopic and clinicopathological features of the lesions were analyzed to provide information of diagnostic value. The GA-FG-CCPs were classified into two categories: submucosal tumor shape (60 %) and flat or depressed type (40 %). Endoscopically, the most common features were submucosal tumor shape (60 %), whitish color (70 %), dilated vessels with branching architecture (50 %), and background mucosa without atrophic change (90 %). GA-FG-CCP has distinct endoscopic characteristics, especially in terms of shape, color, vessels, and background mucosa and may be classified into two categories macroscopically. To diagnose GA-FG-CCP correctly by pathological examination of biopsy specimens, these endoscopic features should be taken into consideration.

Gastric adenocarcinoma of the fundic gland type (GAFG) and pyloric gland adenoma (PGA) have recently been recognized as rare types of neoplasia. We performed comparative immunohistochemical and genetic analyses of 3 GAFGs and 12 PGAs. All of the 3 GAFGs were diffusely positive for pepsinogen-I, MIST1 and MUC6, indicating the predominantly chief cell/mucous neck cell differentiation of these tumors. A small number of H.K-ATPase-positive parietal cells were also scattered. PGAs invariably exhibited diffuse MUC6 and TFF2 expression, consistent with the pyloric gland differentiation of these tumors. Ten of the 12 PGAs also unexpectedly exhibited focal expression of pepsinogen-I and MIST1, suggesting that PGAs often show focal chief cell differentiation and phenotypically resemble mucous neck cells rather than pyloric glands. The mutation analyses revealed activating GNAS mutations, which have been reported to be frequently detected in PGAs, in two of the GAFGs. While GAFGs and PGAs are morphologically distinct lesions, our observations showed their partially overlapping immunohistochemical profiles and shared presence of GNAS mutations, in addition to their common occurrence in the fundic gland mucosa. Based on these observations, we suggest that both GAFGs and PGAs are closely related lesions characterized by a mucous neck cell/chief cell lineage phenotype.

Helicobacter pylori gastritis Molecular pathology of gastric cancer (GasCa) Screening for H. pylori infections Circulating GasCa biomarkers Circulating GasCa cells

The incidence of Helicobacter pylori-negative gastric cancer (HpNGC) is extremely low. A 78-year old female without H. pylori infection was diagnosed with type 4 advanced-stage gastric prepylorus cancer. Distal gastrectomy was performed as for HpNGC (cT3N0M0). Histological findings of the resected specimen showed poorly differentiated adenocarcinoma and signet ring cell carcinoma, which were located in the pyloric gland area, diffusely invaded beyond the serosa without lymph node metastasis (pT4aN0M0). Most cases of undifferentiated-type HpNGC are diagnosed in the early stage and are located in the fundic gland area. We report the first case of advanced-stage undifferentiated HpNGC located in the pyloric gland area.

There are three types of glands in the stomach. They are cardiac, fundic, and pyloric glands.

This study showed that we need to bear in mind the possibility of gastric adenocarcinoma of the fundic gland type upon encounter with such elevated lesions originating from Helicobacter pylori (H. pylori)‐negative gastric mucosa. We believe that our study makes a significant contribution to the literature because small invasive gastric adenocarcinoma of the fundic gland type is a rare disease entity, which exhibits a submucosal tumor‐like or superficial flat‐type elevated lesion on H. pylori‐negative gastric mucosa in the endoscopic examinations.

This study showed that we need to bear in mind the possibility of gastric adenocarcinoma of the fundic gland type upon encounter with such elevated lesions originating from Helicobacter pylori (H. pylori)-negative gastric mucosa. We believe that our study makes a significant contribution to the literature because small invasive gastric adenocarcinoma of the fundic gland type is a rare disease entity, which exhibits a submucosal tumor-like or superficial flat-type elevated lesion on H. pylori-negative gastric mucosa in the endoscopic examinations.

We studied peculiarities of cell reorganization of the gastric transplant during the delayed period after esophagoplasty for benign pathologies of the esophagus. Polymorphism of adaptive and pathological structural rearrangements in the mucosa of the gastric tube was observed. Degenerative and atrophic changes in epithelial structures, hypertrophy of smooth muscular components, and sclerotic reorganization of the stroma were predominating morphological phenomena. Heterogeneity of ultrastructural modifications of the epithelium reflected high secretory activity of foveal mucocytes in combination with degenerative changes in cytoplasmic organelles and impaired secretory function of fundic gland cells. Hypertrophied cells with minor ultrastructural changes, leiomyocytes with signs of biosynthesis, and degenerated smooth muscle fibers were revealed in the population of smooth muscle cells.

We report three cases of adenoma associated with sporadic fundic gland polyp (FGP) in the non-atrophic fundic gland mucosa without Helicobacter pylori (HP) infection, which was verified with both serological and histopathological examinations. Gastric tubular adenoma (flat adenoma) is common and focal cancers occurring in the hyperplastic polyp of foveolar cell type are also sometimes experienced. However, adenomas occurring in sporadic FGP are valuable, as they are very rare, in upper gastrointestinal endoscopy. Whether or not these adenoma lesions of three sporadic FGP cases may become the background of protruded gastric cancers without HP infection remains unclear. Therefore, we emphasize the importance of histological examination on fundic gland polyps that are > 5 mm in size to accumulate new similar cases. Follow-up studies of these lesions are also needed to evaluate their outcomes.

Linitis plastica is a gastric cancer of diffuse histotype that presents in the fundic gland area, and is characterized by thickening of the stomach wall and deformation of the stomach, resulting in a leather bottle-like appearance. A 66-year-old female was admitted to Kagawa University Hospital (Kagawa, Japan) with epigastric pain. X-ray examination revealed reduced gastric distension and deformation of the stomach, which exhibited a leather bottle-like appearance. Endoscopy indicated a depressed lesion in the gastric antrum, and abnormal folds, which crossed to form a waffle-like appearance in the upper gastric body. Analysis of biopsy specimens from the depressed lesion revealed a poorly differentiated adenocarcinoma. Morphological changes in the gastric folds indicated that the tumor had invaded the upper gastric body, therefore, a total gastrectomy was performed. Subsequent pathological findings demonstrated that the tumor had spread from the primary lesion to the upper gastric body. Therefore, the present report recommends that the diagnosis of the spread of linitis plastica-type gastric cancer should include assessments of the primary lesion, as well as evaluation of morphological changes in the gastric folds.

Rationale:Gastric adenocarcinoma of fundic gland type (GA-FG) is a new histological type of gastric cancer manifesting with differentiation into a fundic gland. Furthermore, gastric adenocarcinoma of fundic gland mucosa type (GA-FGM) is a tumor that shows differentiation into not only a fund

Only a few cases of gastric adenocarcinoma of fundic gland type have been reported. Gastric adenocarcinoma with chief cell differentiation (GA-CCD) has been recently reported as a new variant of gastric adenocarcinoma. However, its clinicopathologic features are uncertain. To elucidate them, GA-CCDs exhibiting pepsinogen-I expression (10 lesions: Group A) and randomly selected gastric adenocarcinomas of differentiated type (111 lesions: Group B) were evaluated in this study. Cell differentiation by MUC2, MUC5AC, MUC6, CD10, pepsinogen-I, H+/K+-ATPase and chromogranin A, cell proliferation by Ki-67, and overexpression of p53 protein were evaluated immunohistochemically. In Group A, all GA-CCDs were located in the upper third of the stomach. Tumors were small, with the average maximum diameter ranging from 4 to 20 (average, 8.6) mm. Histologically, GA-CCDs were well-differentiated adenocarcinomas composed of pale gray-blue, basophilic columnar cells with mild nuclear atypia, resembling chief cells. Immunohistochemically, scattered positivity for H+/K+-ATPase was observed in addition to expression of pepsinogen-I and MUC6, indicating focal differentiation toward parietal cells. In Group B, pepsinogen-I was very focally expressed in 2 cases. As these 2 cases exhibited different clinicopathological and histologic features, they cannot be categorized as GA-CCD. Mild atypism, no lymphovascular invasion, low proliferative activity, no overexpression of p53, and no recurrence indicated less aggressiveness of GA-CCD. GA-CCD is rare, but it has distinct clinicopathological characteristics, especially in terms of tumor location, histologic features, phenotypic expression, and low-grade malignancy. We propose gastric adenocarcinoma of fundic gland type (chief cell predominant type) as a new entity of gastric adenocarcinoma.

The Fundic glands of the stomach of Zebra were histochemically analyzed by conventional and lectin histochemistry. The surface mucous cells (SMC) and foveolar mucous cells (FMC) were highly rich with glycoprotein (GPs) with oxidizable vicinal diols and/or glycogen and GPs with carboxyl groups and/ or GPs with O-sulphate esters. The GPs with oxidezable vicinal diols and/or glycogen were predominates in FMC while, the GPs with carboxyel groups and/ or GPs with o-sulphate esters were predominate in SMC. The glandular epithelium of the base region of the fundic gland was devoid of both types of the GPs. All mucous secretig cells (SMC, FMC, mucous neck cells (MNC) and glandular mucous cells (GMS) were highly rich with α- anomer of the N-acetylgalacto-samine (αGalNAc), N- acetyl- glucosamine (GlcNAc) and neuroaminic acid (NeuNAc). The SMC and FMC were devoid of α- D-glucose (α- D- Glc), αD- mannose (α- D- Man), galac-Tose (Gal) and β- anomer of the Nacetylgalactosamine (β- GalNAc). The parietal cells (PC) appeared to react with Helix pomatia agglutinin (HPA), wheat germ agglutinine (WGA) and peanut agglutinin (PNA) indicating the existence of α- and β- anomer of the GalNAc and NeuNAc.

Information on the digestive system of the reptiles is based on relatively few studies on some of the now present 7500 reptilian species. Yet, the gap between our understanding of the major similarities and / or differences between the mammalian and reptilian digestive system does not seem satisfiable. The aim of the current study was to investigate the morphological structure of one of the most common reptilian species in Egypt, Varanus niloticus or Nile monitor. Specimens for histological examination were collected from the esophageus, stomach and small intestine of the Nile monitor and pro-cessed for paraffin embedding. Sections were stained with haemat-oxylin and eosin for general morpho-logy. Periodic Acid Schiff's (PAS) and Alcian Blue (AB) staining methods were applied to detect the different types of the mucous contents of the gastro-intestinal tract. Some paraffin sections were stained with Grimelius silver impregnation technique for localization of the enteroendocrine cells. The folded esophageal mucosa had ciliated columnar epithelium with mucous secreting goblet cells, which stained positive with PAS and AB. The esophageal mucosa was folded and the lining epithelium was ciliated columnar epithelium with mucous secreting goblet cells, which stained positive with PAS and AB. The stomach was divided into fundic and pyloric regions. The mucosa was thrown into gastric pits, into which the gastric glands opened. The surface epithelium was mucous secreting columnar cells and stained positive with PAS but negative with AB. The fundic gland was made by oxynticopeptic cells and few mucous cells, while the entire pyloric gland was made by mucous cells stained positive for both PAS and AB. The small intestine showed many villi but occasional poorly developed intestinal crypts were. The intestinal mucosa was lined with absorptive columnar epithelium with goblet cells, which stained positive with PAS and AB. Enteroendocrine cells were of different shapes; rounded, spindle, oval or

Fundic gland polyps can appear sporadically or in association with familial adenomatous polyposis syndrome. An association between fundic gland polyps and prolonged treatment with proton pump inhibitors has been described, as has their regression after withdrawal of these inhibitors. Dysplastic components are not usually associated. We describe four patients who were receiving chronic treatment with proton pump inhibitors. The results of prior endoscopic analysis were normal. The presence of multiple fundic gland polyps was detected as was their disappearance 6 months after treatment cessation.

We histopathologically re-evaluated the histogenesis of gastric carcinomas from comparative studies between Helicobacter pylori-positive and H. pylori-negative cases using the gastritis score from the Updated Sydney System. The incidence of H. pylori-negative gastric carcinomas was 3.11% (12/386); they are likely to develop in the fundic gland mucosa, and show a gastric phenotype by mucin immunohistochemistry. Even in cases of completely gastric and predominantly gastric phenotypes, CDX2 protein was expressed in most cases (90.9% of pT1 and 100% of pT2-3), indicating a possibility that intestinalization of carcinoma cells occurs independently of the background mucosa. Regarding the degree of gastritis of background mucosa surrounding 143 H. pylori-positive differentiated-type adenocarcinomas, the mean score ranged from 1.497 to 1.713. Our data support the hypothesis that intestinal metaplasia is not a precancerous but a paracancerous lesion, and most gastric adenocarcinomas develop in mildly to moderately atrophic mucosa with H. pylori-infection, i.e., ongoing atrophy.

Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H2 receptor-knockout (H2R-null) mice and an acid exposure model. Age-matched H2R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H2R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H2R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Aims Intraductal papillary mucinous neoplasms (IPMNs) differentiate in several histological directions, which are related to their clinical behaviour. Differentiation of IPMNs to the gastric foveolar epithelium/pyloric gland (PG) is well known. However, no study has been conducted regarding fundic gland (FG) differentiation. The aim of this study was to determine the frequency of FG differentiation and its relationship with the clinicopathological features of IPMNs, by studying 48 surgically resected IPMN cases consisting of 17 gastric IPMNs, 15 intestinal IPMNs, 10 pancreatobiliary IPMNs, and six oncocytic IPMNs. Methods and results Clinicopathological data, including histological tumour grade, immunohistochemical data for mucins (MUCs), pepsinogen I, pepsinogen II, and H,K-ATPase, and GNAS/KRAS status, were analysed. Pepsinogen I and H,K-ATPase were used to assess FG differentiation, and pepsinogen II and MUC6 were used to identify the equivalent cell type of the normal FG. Reverse transcription polymerase chain reaction (RT-PCR) for PGA5/PGC (pepsinogen I and pepsinogen II mRNA, respectively) and quantitative real-time RT-PCR (qRT-PCR) for PGA5 were performed to confirm the immunohistochemistry results. Pepsinogen I expression was detected in 12.5% (6/48) of total IPMNs, of which 66.7% (4/6) of oncocytic IPMNs and 20.0% (2/10) of pancreatobiliary IPMNs were pepsinogen I-positive. No H,K-ATPase-positive cases were detected. Three oncocytic IPMNs with pepsinogen I expression showed similar histology to normal FG. RT-PCR and qRT-PCR confirmed the immunohistochemical results. All IPMNs with FG differentiation were of the oncocytic or pancreatobiliary subtype, were of histologically high grade, and were without GNAS mutation. Conclusions The differentiation of IPMNs to gastric FG is related to oncocytic and pancreatobiliary subtypes, and to high grade. This is the first report to describe differentiation of IPMNs to the FG, and to reveal its relationship with the clinicopathological features of IPMNs.

Nesfatin-1/NUCB2 is a neuropeptide that plays important roles in regulating food intake and energy homeostasis. The distribution of nesfatin-1/NUCB2 protein and mRNA has not been investigated in the canine digestive system. The present study was conducted to evaluate the expression of nesfatin-1/NUCB2 protein and NUCB2 mRNA in the canine digestive organs (esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver and pancreas). The tissues of the digestive system were collected from dogs at different developmental stages (infantile, juvenile, pubertal and adult). Nesfatin-1/NUCB2 protein localization in the organs of adult dogs was detected by immunohistochemistry. The expression of NUCB2 mRNA at the four developmental stages was analyzed by real-time fluorescence quantitative PCR (qRT-PCR). Nesfatin-1/NUCB2 protein was distributed in the fundic gland region of the stomach, and the islet area and exocrine portions of the pancreas. However, NUCB2 mRNA was found in all digestive organs, although the expression levels in the pancreas and stomach were higher than those in liver, duodenum and other digestive tract tissues (P

A male in his eighties attended our hospital for further evaluation of gastric cancer. A gastroscopy revealed a whitish flat elevated lesion (Paris, 0-IIa) of 15 mm in diameter on the greater curvature of the proximal fornix. The preoperative diagnosis was intra-mucosal differentiated gastric cancer, and a novel therapeutic approach, combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET) was applied and the lesion was resected in a single piece without any complications. Histopathological findings revealed atypical glandular epithelium proliferated in the mucosa and shallow layer (300 μm) of submucosa. These cells stained positive for pepsinogen-I and the final diagnosis was gastric cancer of fundic gland type (GAFT). There was no lymph–vascular involvement and free horizontal and vertical margins were confirmed. CLEAN-NET could be a therapeutic option for GAFT at low risk of lymph node metastasis because it prevents excess wall defect and exposure of cancer cells into the peritoneal cavity.

An asymptomatic 79-year-old man had been undergoing esophagogastroduodenoscopy annually since having an endoscopic resection of an intramucosal welldifferentiated gastric adenocarcinoma of the middle body 9 years previously. He hadalso receivedHelicobacter pylorieradication therapy,which had been successful, 10 years previously. On this occasion, his follow-up esophagogastroduodenoscopy revealed a minute submucosal tumor-like polypoid lesion with some whitish discoloration on the greater curvature of the gastric lower body (●" Fig.1a). Narrow-band imaging showed non-neoplastic pits that were slightly dilated (●" Fig.1b). Complete resectionwas attempted using a deep biopsy procedure because a carcinoid tumor was suspected and the size of the lesion was small (approximately 1.6mm in diameter by comparison to the forceps) (●" Fig.1c). Histological examination of the biopsy specimen revealed atypical tubules made up of cells with basophilic cytoplasm (●" Fig.2). These were covered with a non-neoplastic epithelium and were invading the muscularis mucosae with fibromusculosis. No lymphovascular invasion was observed. Immunohistochemical analysis revealed that these tubules were diffusely positive for pepsinogen I and MUC6, positive for H+/K+ ATPase in scattered locations around the tumor margin, and negative for MUC2, MUC5AC, CD10, and chromogranin A. The patient was diagnosed with gastric adenocarcinoma of the fundic gland, chief cell predominant type. Endoscopic submucosal dissection was performed, but no remnants of the tumor were present. No evidence of metastasis was observed on a computed tomography (CT) scan 1 year later. Gastric adenocarcinoma, fundic gland type (GA-FG) has recently been proposed as a new entity of gastric adenocarcinoma [1]. GA-FG chief cell predominant types (GA-FG-CCPs) mostly develop without Helicobacter pylori infection [2] and often invade the submucosa independently of size [1,2]. Endoscopically, early GA-FG-CCPs may mimic early carcinoid tumors because both of these tumors are histologically centered in the deep mucosa (●" Fig.2) [3]. It has been reported on endoscopic evaluation that half of GA-FG-CCPs have a submucosal tumor shape with a whitish color [2]. Our case suggests that the early features of GA-FG-CCP include the above characteristics.

In this chapter, we are demonstrating representative magnifying endoscopic findings with NBI of gastric neoplastic lesions according to VS (vessel plans surface) classification system. The neoplastic lesions are adenoma, early cancers, MALT lymphoma and carcinoid.

In this chapter, we described magnifying endoscopic findings with NBI of non neoplastic lesions in the duodenum mainly focussing on gastric metaplasia.

The present work was carried out on 20 specimens of both sexes of Nile catfish in order to observe the morphological and histological as well as the fine structure of fundic gland region of the stomach. The present study demonstrated the presence of folded mucosa in the fundic region of the stomach and its surface epithelium was lined by simple columnar mucosecretory cells. The lamina propria contained simple tubular branched glands. The fundic glands were made up of oxyntico-peptic cells. The glandular cells were positive to PAS and negative to Alcian blue and showed strong positive activity for acid phosphatase. The electron microscopic examination revealed that the oxyntico-peptic cells contained a dense tubulovesicular system that may participate in hydrochloric acid production, in addition to the extensive presence of mitochondria and rough endoplasmic reticulum. The Golgi complex is involved in the formation of secretory or zymogen granules. Oval to round- shaped enteroendocrine cells were scattered among the glandular and superficial columnar cells, which stained positive to Grimelius stain. The glands were surrounded by collagenous fibers and smooth muscle fibers

Background: Gastric type adenocarcinoma with fundic gland differentiation (GA-FG) has been reported as a new, rare, chief cell differentiation composed carcinoma. Clinicopathologically, it exists on the gastric cardia/fundus, with low proliferative activity and low-grade malignancy. Until now, there has been no report of this GA-FG type cancer in the duodenum. We firstly planned to resect the tumor with endoscopic mucosal resection with a cap-fitted endoscope (EMR-C). Nevertheless a large amount of 0.4% sodium hyaluronate solution was injected into the submucosal layer because mucosal lesions could not be adequately lifted. A 67-year-old male was routinely seen at a hospital after a rectal cancer operation in December 2005. Every year he received a GI fiber examination. Five years after the operation, gastric endoscopic examination revealed a small nodular lesion at the bulbus, and subsequently a mucosal biopsy was performed (Figure 1a). Microscopically, the biopsy specimen demonstrated characteristics of gastric adenocarcinoma of fundic gland type. Laboratory examinations revealed that all parameters were within normal limits. CT scan showed no duodenal wall invasion to pancreas and no lymph node metastases. Case presentation: In this case, we report a case that coincidentally diagnosed GA-FG neighboring to Brunner’s glands hyperplasia in the duodenum, and successfully resected by ESD (Endoscopic Submucosal Dissection). Unfortunately, owing to a thin submucosal, pin hole perforation was caused while snaring the tumor. Endoscopic 4 clippings, expelled remaining abdominal air, and 2 weeks non oral in take was cured acute peritonitis. Conclusions: We report the experience of the rare case of Gastric type adenocarcinoma with fundic gland differentiation in the duodenum, arising from Brunner’s gland hamartoma / hyperplasia, resected by ESD (Endoscopic Submucosal Dissection).

This study used mucin immunohistochemistry to investigate differences in the properties of intestinal metaplasia between the antrum and body of the stomach in 28 resected specimens. Intestinal metaplasia was classified as: (1) small intestinal metaplasia (SIM) with a tubule, including CD10-positive brush border on a background of MUC5AC-/ HGM-negative cells; or (2) goblet cell metaplasia (GCM) with MUC2-positive and CD10-negative cells. In the antrum, frequencies of SIM and GCM were nearly equal irrespective of metaplasia grade. Frequency and length of remnant pyloric gland for SIM were significantly greater in the antrum than in the body. In the proliferative zone, there existed a lower level in SIM than in non-intestinalized tubules. These findings suggest that the proliferative zone shifts from the neck zone toward the bottom of the tubule during the SIM process in the antrum. In the body, however, the grade of SIM grade was significantly higher than that of GCM. The proliferative zone was located higher in the fundic gland, pseudopyloric gland and SIM, in that order. Almost all remnant pyloric glands for SIM were negative for pepsinogen I. These facts indicate that SIM in the body originates in a proliferative zone that shifted downward to an area near the bottom of the tubule, with atrophic pyloric glands originating from pseudopyloric gland metaplasia.

Sonic hedgehog (Shh) is a morphogen involved in many aspects of patterning of the gut during embryogenesis and in gastric fundic gland homeostasis in the adult. Intestinal metaplastic change of the gastric epithelium is associated with the loss of Shh expression, and mice that lack Shh expression show intestinal transformation of the gastric mucosa. The present study was designed to investigate the alteration of Shh expression in the stomach of an experimental model of Helicobacter pylori (H. pylori) colonization. Male Mongolian gerbils were inoculated with H. pylori and examined 4 and 51 weeks later. The level of Shh mRNA expression was determined by quantitative RT-PCR and in situ hybridization. Shh protein expression was determined by immunoblotting and immunohistochemistry. Shh was expressed in the parietal cells, zymogenic cells, and mucous neck cells of the gastric fundic glands of gerbils. Prolonged colonization by H. pylori led to extension of the inflammation from the antrum to the corpus of the stomach, with loss of Shh expression. Loss of Shh expression correlated with loss of parietal cells, disturbed maturation of the mucous neck cell-zymogenic cell lineage, and increased cellular proliferation. Shh expression is significantly reduced in H. pylori-associated gastritis. These data show for the first time that H. pylori infection leads to down-regulation of the expression of a morphogen with an established role (Shh) in gastric epithelial differentiation.

VacA was histochemically stained in biopsy specimen and was intracellularly and mainly located in fundic gland area. It is recognized gastric atrophy was observed in the H. pylori-positive patients with intracellular VacA compared with others. The aim of study is to understand the relationship between intracellular VacA and the progression of gastric atrophy that is associated with gastric cancer. Biopsy specimens and sera were obtained from 364 people in their 50s and 60s without gastric cancer diagnosed at first endoscopy undergoing diagnostic endoscopy, for H. pylori infection, histology, and the histochemical status of intracellular VacA using anti-VacA Ab during the follow-up period (mean, 7.3 years). Three hundred eleven of 364 enrolled patients were H. pylori positive and 53 patients were H. pylori negative at first endoscopy. VacA was intracellularly stained with vacuolation and cell destruction in the fundic gland in 98 of 311 H. pylori-positive patients and not stained in another 213 H. pylori-positive patients plus 53 H. pylori-negative patients at first endoscopy. Gastric atrophy has significantly progressed in the H. pylori-positive patints with intracellular VacA with gastric ulcers compared with the others and six gastric cancers have developed in this group during the follow-up period (mean, 7.3 years). Intracellular VacA is a valuable marker to predict whether Helicobacter pylori induces progressive atrophic gastritis that is associated with the development of gastric cancer.

We report a patient with familial adenomatous polyposis who developed high-grade dysplasia against a background of fundic gland polyposis. Two large high-grade dysplasia lesions were found in the gastric body, where numerous fundic gland polyps were present. In both lesions, the dysplastic epithelium covered non-neoplastic oxyntic glands that occasionally exhibit cystic changes. A genetic analysis for APC (adenomatous polyposis coli) revealed a somatic 50-bp deletion involving codons 1502-1517 and 2-bp deletion at codon 1465 in each lesion of high-grade dysplasia. In contrast, six of the 18 fundic gland polyps were found to harbor an identical mutation: 1-bp insertion at codon 1556. Both lesions of high-grade dysplasia and the fundic gland polyps were similarly located in the fundic gland area and were caused by the inactivation of APC; however, their mutation profiles of APC were different. These results imply that fundic gland polyps and high-grade dysplasia of the stomach have distinct preferences for APC genotypes in their development.

Gastric ulcers in humans are notoriously chronic and recurring lesions. Although the average individual who undergoes no treatments requires many years for healing, most studies on the healing process of the experimentally induced ulcers have mainly focused on the early stages. Natural history of the ulcer healing has not been completely revealed. We have undertaken long-term investigation up to the 150th day after the cryo-injury to shed light on the natural history of the ulcer healing process compared with developmental changes of postnatal fundic glands. By the 30th day, restitutive gastric glands were mostly seen to cover the ulcer lesions, where well-developed gland-type mucous cells, showing Griffonia simplicifolia agglutinin (GSA)-II labeling, appeared to occupy the basal portion. Most of the bromodeoxyuridine-labeled cells were superimposed on the GSA-II-positive cell zone, forming the proliferative zone. By the 150th day, the restitutive glands were complete, with all epithelial components and topology of the normal fundic glands. The process of the ulcer healing was quite compatible with the developmental changes of the postnatal fundic glands. These results imply that the regeneration of gastric epithelium during the ulcer healing follows pathways linked to the ontogenetic course of the fundic gland.

Sporadic fundic gland polyps account for approxmately 50% of all gastric polyps and may be observed in .8% to 1.9% of patients undergoing upper gastrointesinal endoscopy (Table 1).1,2 They are encountered more ommonly in middle-aged women, although they are lso observed in men and in about 0.3% of pediatric atients undergoing endoscopy with an average age of iagnosis of 14.4 years.3 Fundic gland polyps also occur n 12.5% to 84% of patients with familial adenomatous olyposis (FAP).4 In this setting the occurrence is equivlent in women and men and polyps are observed at uch younger ages. Fundic gland polyps may be single or multiple, but sually fewer than 10 polyps are observed in the sporadic etting, although 50 or more polyps have been reported. hese polyps always occur in the body and fundus of the tomach. In FAP, numerous fundic gland polyps are sually observed, often numbering in the hundreds (Figres 1A–B). The polyps may cover the entire surface of he acid-secreting epithelium and even coalesce to give a matted” appearance of the mucosal surface. Polyps in oth the sporadic setting and in FAP are usually 1-mm o 5-mm in diameter, although larger polyps are oberved. They are sessile, hemispherical-shaped elevations, ith the occasional appearance of a “waist” but not a talk. Their color is pale pink, resembling surrounding ucosa. At endoscopic biopsy the polyps usually “chunk ff” or detach entirely at the base, unlike other gastric olyps. These characteristics together usually make funic gland polyps endoscopically distinguishable from ther types of gastric polyps.1 Histologically, fundic gland polyps are characterized y cystically dilated and irregularly budded fundic lands, which are lined by flattened parietal cells, chief ells, and variable numbers of mucous neck cells.4 The verlying surface and foveolar gastric epithelium is typcally nondysplastic. Surrounding mucosa is uniformly ormal both morphologically and histologically and conurrent atrophy is seldom observed. The pathogenesis and cancer risk of fundic gland olyps is poorly understood. These lesions have usually een considered hamartomas, although up to 25% of AP-associated fundic gland polyps and 1% of sporadic ypes are now known to show foveolar epithelial dysplaia, which is often proceeded by dysregulation of epitheial proliferation.5 Gastric cancer has been reported in AP patients with fundic gland polyps, even arising rom them,6,7 although the lifetime risk of gastric cancer n FAP is estimated to be only 0.6%,8,9 but may be igher in some countries such as Japan.10 Fundic gland polyps in FAP arise from mutational nactivation of the adenomatous polyposis coli (APC) ene, which is the gene mutated in that condition,2 hile sporadic fundic gland polyps are usually caused by ctivating mutations of the beta-catenin gene.4,11 Both enes are involved in the same cell growth-signaling athway,12 which explains why mutations in either gene an give rise to fundic gland polyps that are histologially similar. When dysplasia occurs in fundic gland olyps it is usually in polyps with mutations of the APC ene. This observation appears to explain why dysplasia s sometimes observed in the fundic gland polyps of FAP, ut seldom in sporadic fundic gland polyps.13 c

The most common types of benign gastric polyps are fundic gland polyps, hyperplastic polyps, and adenomas. The aim of this study was to determine on which morphological and functional background benign gastric polyps develop. The study includes 85 consecutive patients with gastric polyps and sex- and age-matched controls without polyps selected at random from a general population sample. The type of polyp was hyperplastic in 52 (61%), fundic gland in 18 (21%), adenoma in 10 (12%), carcinoid in 2 (2%), hamartoma in 2 (2%), and inflammatory fibroid in 1 (1%) of the cases. Routine biopsies from the gastric corpus and antrum were examined for presence of gastritis and H. pylori. Blood samples were analyzed for H. pylori antibodies, H+,K+-ATPase antibodies, gastrin, and pepsinogen I. Patients with hyperplastic polyps had increased P-gastrin concentrations and S-H+,K+-ATPase antibody titers and decreased S-pepsinogen I concentrations with a high prevalence of atrophic corpus gastritis or pangastritis. A similar pattern was observed among patients with adenomas, whereas patients with fundic gland polyps had normal serology and a lower prevalence of gastritis and H. pylori infection than controls. In conclusion, hyperplastic polyps and adenomas are generally associated with atrophic gastritis. Patients with fundic gland polyps seem to have a sounder mucosa than controls. Whereas the risk of malignant gastric neoplasia is increased in patients with hyperplastic polyps or adenomas, this does not seem to be the case in patients with fundic gland polyps.

Background: Phospholipids play an important role in gastric mucosal protection. The purpose of the present study was to investigate changes in various phospholipids in the fundic and pyloric gland mucosae of patients with gastric mucosal disease. Methods: One hundred and five patients with superficial gastritis, duodenal ulcer, gastric ulcer or gastric cancer were studied. Patients underwent endoscopy to obtain biopsy specimens from both the fundic and pyloric gland mucosae. The phospholipid contents were measured by high performance liquid chromatography. Results: Total phospholipid level was significantly greater in the fundic gland mucosa than in the pyloric gland mucosa (P = 0.037), and the level in the fundic gland mucosa was high in all four gastric diseases studied. The difference was significant in patients with gastric ulcers (P = 0.0156). Total phospholipid levels were the highest in superficial gastritis, followed by duodenal ulcer, gastric ulcer and gastric cancer. In all four gastric diseases, phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) levels were high, while phosphatidylinositol, lysophosphatidylcholine, and sphingomyelin levels were low. The PE and PC levels were higher in the fundic gland mucosa than in the pyloric glandular mucosa, whereas the PS level was higher in the pyloric gland mucosa than in the fundic gland mucosa. Conclusions: The fundic gland mucosa has stronger phospholipid-related protection than the pyloric gland mucosa, based on the levels of mucosal phospholipids. The main phospholipids for gastric mucosal protection are PC and PE (in the fundic gland mucosa) and PS (in the pyloric gland mucosa). Phospholipid-related protection is strong in superficial gastritis and duodenal ulcer, but is reduced in the pyloric gland mucosa in patients with gastric ulcers, and in both gastric gland mucosae in patients with gastric cancer.

After oral and intravenous administration of [ 14 C]clarithromycin to rats, c. 60-70% of the radioactivity in the gastric tissue was found to be distributed in the mucosal layer. Co-administration of lansoprazole and amoxicillin had no apparent effect on this distribution pattern of [ 14 C]clarithromycin. The amount of unchanged [ 14 C]clarithromycin in gastric contents increased with co-administration of lansoprazole and amoxicillin. Microautoradiograms of the gastric mucosa showed that [ 14 C]clarithromycin was highly distributed in the mucous layer and in surface epithelial cells following oral administration. Homogeneous distribution of radioactivity was evident in the fundic gland. With iv administration, [ 14 C]clarithromycin seemed to be secreted by both secreting cells in the gland base and surface epithelial cells.

The CDX1 and CDX2 genes are intestinal transcription factors that may be involved in the regulation of proliferation and differentiation of intestinal epithelial cells. There have been no detailed reports directly comparing the expression of CDX1 with that of CDX2 in chronic gastritis and intestinal metaplasia. Accordingly, we examined the expression of CDX1/2 and its association with the expression of other intestinal metaplasia-associated genes during the development of intestinal metaplasia. Methods. The expression of CDX1/2 genes was analyzed, using the reverse transcriptase-polymerase chain reaction, in 44 human gastric tissue samples obtained endoscopically. The expressions of mucin markers (MUC2, MUC5AC), intestine-specific genes (sucrase-isomaltase, human defensin-5, alkaline phosphatase), a gene marker for fundic gland area (H+/K +ATPase β subunit), and a gene for entire gastric glands (pepsinogen C) were also comparatively analyzed. Results. There was no expression of CDX1/2 in gastric mucosa not infected by Helicobacter pylori. The prevalence of CDX1 mRNA expression was significantly higher in mucosa with intestinal metaplasia than in mucosa without intestinal metaplasia. It is noteworthy that CDX2 was expressed in the antral and fundic mucosa in the absence of the expression of CDX1 and gene markers for intes-tinal metaplasia. Conclusions. The expression of CDX2 precedes those of CDX1, sucrase-isomaltase, other intestine-specific genes (human defensin-5, alkaline phosphatase), and MUC2 during the progression of intestinal metaplasia. These findings imply that the expression of CDX2 may trigger the initiation and development of intestinal metaplasia.