Differentiated adenocarcinoma with a gastric phenotype in the stomach: difficulties in clinical and pathological diagnoses

Differentiated-type adenocarcinoma with gastric phenotype of the stomach is rare and is difficult to diagnose both clinically and pathologically. We report a case of differentiated-type adenocarcinoma with a gastric phenotype in the stomach. A 60-year-old Japanese female was referred to our hospital with gastric cancer. A barium meal examination and esophagogastroduodenoscopy revealed a granular elevated lesion in the lower body near the lesser curvature and a depressed lesion on the antrum. A biopsy specimen showed benign atrophic mucosa in a granulated lesion and moderately differentiated adenocarcinoma in the depressed lesion. The patient underwent laparoscopy-assisted distal gastrectomy with lymph node dissection. The postoperative course was uneventful. Histological examination of the resected tissue confirmed well-differentiated adenocarcinoma in the granulated lesion and moderately differentiated adenocarcinoma in the depressed lesion, without lymph node metastasis. Both lesions were confined to the mucosa. Since mucin immunohistochemistry revealed MUC5AC-positive staining in the granulated lesion, the final diagnosis was differentiated-type adenocarcinoma with gastric phenotype in the stomach. Despite the high malignant potential, the clinical and pathological diagnoses of gastric-type differentiated adenocarcinoma are often difficult. Mucin immunohistochemistry together with hematoxylin and eosin (HE) staining may be helpful in the pathological diagnosis of this rare disease.     

Mucin phenotype of gastric cancer and clinicopathology of gastric-type differentiated adenocarcinoma

Differentiated adenocarcinoma of the stomach is classified into gastric or intestinal phenotypes based on mucus expression. Recent advances in mucin histochemistry and immunohistochemistry have highlighted the importance of such a distinction, and it is important clinically to distinguish between gastricand intestinal-type differentiated adenocarcinoma. However, a clinical and pathological diagnosis of this type is often difficult in early gastric cancer because of histological similarities between a hyperp...     

Correlation between cyclooxygenase-2, proliferative activity,and mucin phenotype in human advanced gastric cancer

Background Recent studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancer, and that cyclooxygenase-2 (COX-2) may be a target enzyme for the prevention or regression of cancer by the use of NSAIDs. Mucin histochemistry has made possible a clear distinction between the differentiated characteristics of gastrointestinal epithelial cells, and the possibility that phenotypic shifts from gastric- to intestinal-type in gastric carcinoma progression has been suggested. To evaluate the role of COX-2 in gastric cancer progression, we immunohistochemically investigated COX-2 expression, and examined its relationship to proliferative activity, mucin phenotype, and clinicopathological parameters in human advanced gastric carcinomas.Methods Forty-five surgical specimens of advanced gastric carcinomas (invaded the muscularis propria or subserosa) were examined. Immunohistochemical staining was performed with monoclonal antibodies against COX-2, Ki-67, CD10 (brush border), MUC-2 (goblet-cell mucin), MUC-5AC (gastric foveolar mucin), and MUC-6 (pyloric mucin). COX-2 expression was scored by the percentage of COX-2-positive neoplastic cells, and proliferative activity was assessed by the Ki-67 labeling index at the deepest area of invasion. The mucin phenotype of the carcinomas was classified into three categories; gastric, intestinal, and unclassified.Results COX-2 staining was restricted to the cytoplasm, not only in cancer cells but also in intestinal metaplasia and some inflammatory cells and COX-2 expression in cancer cells varied greatly, but the staining in some samples was preferentially found at the invasive front. COX-2 positivity was found to correlate with Ki-67 labeling. The mean COX-2 scores were 2.29%, 2.71%, and 2.75%; and the Ki-67 labeling indices were 23.6%, 40.6%, and 56.5%, in gastric-, intestinal-, and unclassified- type carcinomas, respectively.Conclusions A close relationship between COX-2 expression and proliferative activity was confirmed in the deepest areas of advanced gastric carcinoma, and the proliferative activity increased from gastric- to intestinal- and to unclassified- type gastric carcinoma, suggesting a role for COX-2 expression and differences in biological behavior according to mucin phenotype expression during gastric cancer progression.     

Confocal endomicroscopy for phenotypic diagnosis of gastric cancer

Background and Aim: Relationships between mucin phenotype and malignant potential in gastric cancers have attracted attention. We attempted to assess the possibility of obtaining phenotypic diagnoses by confocal endomicroscopy. Methods: Confocal images of target lesions were obtained in 29 of 40 patients with gastric cancer. Appearances of the brush border, goblet cells, and gastric foveolar epithelium were investigated with immunohistochemical staining using CD10, MUC2, and human gastric mucin to evaluate phenotypic expression in gastric carcinomas. Confocal images were compared with immunohistochemical findings for goblet cells and brush borders. Results: Both the endoscopists and the pathologist obtained high accuracy rates for differential diagnosis. Sensitivity and specificity for goblet cells were 85.7% and 92.3% (Endoscopist A), and 85.7% and 88.5% (Endoscopist B). The κ‐value for correspondence between two endoscopists for the diagnosis of goblet cells in confocal images was 0.73. Sensitivity and specificity for the brush border were 93.8% and 91.7% (Endoscopist A), and 81.3% and 91.7% (Endoscopist B). The κ‐value for correspondence between two endoscopists for diagnosis of the brush border in confocal images was 0.79. Intestinal phenotypic gastric cancers show a brush border, goblet cells, or both. Sensitivity and specificity for the intestinal phenotype in confocal endomicroscopy were 90.9% and 77.8% (Endoscopist A), and 86.4% and 83.3% (Endoscopist B). Conclusion: The confocal endomicroscopic diagnosis of the mucin phenotype in gastric cancers was limited to intestinal and mixed phenotypes, but may be useful for the diagnosis of mucin phenotype and differential diagnosis.     

Pedunculated gastric carcinoma demonstrating a gastric foveolar phenotype

We report a case of gastric cancer complicated with very well differentiated adenocarcinoma containing signet ring cells. An endoscopic examination revealed a pedunculated polyp in the fornix of the stomach. A surgical operation was performed and the pathological findings showed very well differentiated adenocarcinoma mimicking gastric foveolae with a poorly differentiated component containing signet ring cells. This is the first case of pedunculated gastric cancer complicated with very well differentiated adenocarcinoma containing signet ring cells and also demonstrating a gastric foveolar phenotype.     

Evaluation of mucin expression patterns in gastric borderline (group III) lesions

Background Recommendations for diagnosis and treatment of gastric borderline (group III) lesions remain controversial. We examined mucin expression patterns in endoscopically resected and forceps biopsy samples. Methods Sixty-three gastric lesions were histopathologically identified as belonging to group III on the basis of an endoscopic forceps biopsy. All of the patients underwent endoscopic resection, and the lesions were classified into group A (final diagnosis, adenocarcinoma) or group B (final diagnosis, adenoma). Immunostaining for MUC2, MUC5AC, MUC6, and CD10 was performed and the mucin phenotype determined. An additional 26 forceps biopsy samples from the above 63 patients were similarly evaluated. Results The proportion of complete gastric (positive for MUC5AC and MUC6) plus gastric-predominant phenotypes was significantly higher in group A (58.0%) than in group B (18.7%) lesions (P < 0.05). The proportion of the complete intestinal (positive for MUC2 and CD10) phenotype was significantly higher in group B (68.8%) than in group A (19.4%) (P < 0.05). Similar results were also observed in the 26 forceps biopsy samples histopathologically diagnosed as group III lesions. The proportion of samples with a diffuse Ki-67 immunostaining pattern was significantly higher in group A than in group B (P < 0.05). p53 expression was significantly higher in group A (29.2%) than in group B (4.3%) (P < 0.05). Conclusions Immunostaining of forceps biopsy samples for the mucin phenotype may be helpful for diagnosing gastric borderline (group III) lesions.     

Significant enhancement of gastric mucin content after rabeprazole administration: its potential clinical significance in acid-related disorders

Rabeprazole is the only proton pump inhibitor that enhances the content of gastric mucin in experimental animals. We have studied, therefore, the effect of rabeprazole on the content of gastric mucin, mucus, and its viscosity in 21 asymptomatic volunteers in a double-blind study. The mucus content during rabeprazole administration significantly increased both in pentagastrin-stimulated (3.36 ± 0.39 vs 1.50 ± 0.32 mg/ml, P < 0.001) and basal (3.31 ± 0.38 vs 2.28 ± 0.36 mg/ml, P < 0.01) conditions. The content of mucin during rabeprazole was 2.6-fold (0.96 ± 0.08 vs 0.36 ± 0.06 mg/ml, P < 0.0001) and 41% (0.82 ± 0.09 vs 0.58 ± 0.09 mg/ml, P < 0.05) higher in stimulated and basal conditions, respectively. The viscosity of gastric juice during rabeprazole administration was also significantly higher both in stimulated (P < 0.01) and basal (P < 0.05) conditions. In conclusion, the unique pharmacological property of rabeprazole, significantly augmenting production of gastric mucus and mucin, may translate to additional clinical benefits in protecting the upper alimentary tract mucosa during the acid-related challenge.     

Systemic polyarteritis nodosa as the initial manifestation of a gastric adenocarcinoma

Abstract. We report a case of systemic polyarteritis nodosa (PAN) leading to the discovery of an as yet asymptomatic, surgically curable gastric adenocarcinoma. PAN is rarely associated with malignancies and in such cases these are more often malignant haemato-logical diseases than solid neoplasms. The immuno-pathological findings, the temporal relationship between both conditions, and the spontaneous resolution of vasculitis after tumour removal suggest a paraneoplastic origin of the systemic angitis.     

Erythrocyte Lewis (A+B-) host phenotype is a factor with familial clustering for increased risk of Helicobacter pylori-related non-cardiac gastric cancer

BACKGROUND: The purpose of the present study was to test whether host erythrocyte Lewis phenotypes correlated with the risk of gastric cancers. Because of the association of gastric cancer with familial clustering, cancer relatives were investigated as to whether they had unique distribution of Lewis phenotypes. METHODS: The study prospectively enrolled 74 Helicobacter pylori-positive gastric cancer patients and 100 H. pylori-positive duodenal ulcer patients to serve as non-cancer controls after panendoscopy. In addition, 433 family members from the 74 index cancer and 100 non-cancer control patients were enrolled. All enrolled cases were checked for their H. pylori status and erythrocyte Lewis phenotypes, defined as Le(a-b-), Le(a-b+), Le(a+b-), and Le(a+b+) subtypes by the anti-Le(a) and anti-Le(b) monoclonal antibodies. RESULTS: These H. pylori-infected patients with gastric cancer had a higher rate of Le(a+b-) phenotype and a lower rate of Le(a-b+) phenotype than the non-cancer duodenal ulcer controls (20.3% vs 9%; 51.4% vs 72%, P < 0.05). Among these H. pylori-infected patients, the risk of the patients with Le(a+b-) phenotype having gastric cancer was 3.15-fold higher as compared with those with the Le(a-b+) phenotype (P = 0.02, 95% confidence interval: 1.26-7.87). The offspring and cousins of the cancer patients had a higher rate of Le(a+b-) phenotype as compared to either that of the spouses of cancer index patients or to that of the family members of the non-cancer control (P < 0.05). CONCLUSION: Le(a+b-) phenotype of the H. pylori-infected host could be a risk factor (with familial clustering) for gastric carcinogenesis.     

Metastatic gastric tumor secondary to pancreatic adenocarcinoma

Metastatic disease, from the pancreas, involving the stomach is an unusual clinical event. Local recurrence, liver metastases, and peritoneal spread are the most common recurrent patterns after curative resection of pancreatic cancer. We report a patient who suffered from gastric metastasis secondary to pancreatic adenocarcinoma 1 year after pancreatectomy. A 49-year-old woman underwent distal pancreatectomy with intraoperative radiation therapy for cancer of the body of the pancreas in October 2002. The histological diagnosis was well-differentiated adenocarcinoma of the pancreas, stage IIB; T1N1M0. Multiple liver metastases were detected on computed tomography (CT) in March 2003. Combination chemotherapy of 5-fluorouracil hepatic arterial continuous infusion and systemic gemcitabine administration led to the disappearance of the liver metastases on CT in September 2003. One month later, she complained of epigastric pain and underwent gastric endoscopy, which revealed a submucosal tumor in the fornix posterior wall. Histological diagnosis of the biopsy specimen was well-differentiated adenocarcinoma, and immunohistochemical studies, using anti-cytokeratin 7 and -20 monoclonal antibodies, were compatible with gastric metastasis from pancreatic carcinoma. A F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) scan revealed a high-uptake lesion, which coincided with the gastric tumor. No other abnormal uptake could be found. Histopatholoical examination of the resected specimen revealed submucosal growth of the metastatic cancer (well-differentiated adenocarcinoma).     

Alterations in gastric mucin synthesis by Helicobacter pylori

AIM To determine the role of Helicobacter pylori in altering gastric mucin synthesis and define how thprocess relates to H. pylori-related diseases.METHODS Analyses of human gastric tissues using immunohistochemistry and in situ hybridizatiodocument the role of H. pylori in altering the composition and distribution of gastric mucins.RESULTS These data indicate a decrease in the product of the MUC5 (MUC5AC) gene and aberraexpression of MUC6 in the surface epithelium of H. pylori-infected patients. A normal pattern was restorby H. pylori eradication. Inhibition of mucin synthesis including MUC5AC and MUCl mucins by H. pvlohas been established in vitro using biochemical and Western blot analyses. This effect is not due to inhibitiof glycosylation, but results from inhibition of synthesis of mucin core structures. In vitro experiments usiinhibitors of mucin synthesis indicate that cell surface mucins decrease adhesion of H. pylori to gastepithelial cells.CONCLUSION Inhibition of mucin synthesis by H. pylori in vivo can disrupt the protective mucous layand facilitate bacterial adhesion, which may lead to increased inflammation in thc gastric epithelium.     

Invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma without mucin hypersecretion but with changes in the pancreatic duct on pancreatography

We present a case of invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma without mucin hypersecretion in a 65‐year‐old man with a 45‐year history of alcohol abuse and a 2‐year follow‐up of chronic pancreatitis. Two years previously, in May 1998, he was admitted for investigation of abdominal pain. Computed tomography (CT) showed diffuse dilation of the main pancreatic duct with atrophy of the pancreatic parenchyma. Endoscopic retrograde pancreatography (ERP) showed a diffusely dilated main pancreatic duct with irregular side branches in the head of the pancreas. Chronic alcoholic pancreatitis was diagnosed on the basis of the pancreatography findings. The patient was readmitted for investigation of progressive weight loss in August 2000. Serum CA19‐9 levels were markedly elevated (750U/ml) and CT showed enlargement of the head and body of the pancreas. ERP showed irregularity of the main pancreatic duct in the head of the pancreas, and the distal main pancreatic duct (which was dilated on initial ERP examination) was interrupted in the body of the pancreas. Suspected pancreatic carcinoma was diagnosed, and pylorus‐preserving pancreatoduodenectomy was performed. Frozen section examination of the cut end of the pancreas revealed ductal carcinoma, and total pancreatoduodenectomy with portal vein resection was performed. Histologically, the resected tumor was diagnosed as an invasive carcinoma derived from intraductal papillary adenocarcinoma without mucin hypersecretion. We recommend observing changes in the pancreatic duct on pancreatography to diagnose invasive carcinoma of the pancreas derived from intraductal papillary adenocarcinoma in a resectable state.     

Recovery of mucin content in surface layer of rat gastric mucosa after HCl-aspirin-induced mucosal damage

Quantitative changes in mucin (mucus glyco-protein) in different layers of rat gastric mucosa after mucosal damage induced by acidified acetylsalicylic acid (HCl-aspirin; 0.15N HCl, 20–200 mg acetylsalicylic acid/kg body weight) were studied. More than 50 mg/kg HCl-aspirin led to a significant increase in macroscopic gastric injury (expressed as ulcer index) at 3h, compared with control (no aspirin) and there was a significant recoverly at 7h. Three h after dosing with 50 mg/kg acidified aspirin, there was superficial mucosal damage and decreased mucin content in the surface mucosal layer. Mucin production recovered 7h after the administration of 50 mg/kg acidified aspirin. Doses of acidified aspirin higher than 100 mg/kg decreased mucin content in the surface and deep corpus mucosal layers and no recovery was seen 7h after the administration. Physiological damage after the administration of 50 mg/kg HCl-aspirin was limited mainly to surface epithelial mucus cells. An experimental model in which superficial erosion was induced in rat gastric mucosa was established with low-dose HCl-aspirin.     

Reduction of syndecan-1 expression in differentiated type early gastric cancer and background mucosa with gastric cellular phenotype

Background Syndecan-1 is known to play a role as a cell adhesion molecule, similar to E-cadherin, and is associated with the maintenance of epithelial morphology. The purpose of this study was to elucidate the role and alterations of syndecan-1 expression in comparison with those of E-cadherin in different cellular phenotypes of differentiated-type gastric cancers (DGCs).Methods A total of 80 DGCs at an early stage, and their adjacent mucosa, were evaluated by both immunohistochemistry and in situ hybridization. Syndecan-1 and E-cadherin were assessed by immunohistochemical staining with an anti-syndecan-1 and an anti-E-cadherin antibody, respectively. Based on immunohistochemistry, DGCs and their surrounding mucosa were divided into four types: gastric type (G-type), ordinary type (O-type), complete-intestinal type (CI-type), and null type.Results The expression sites of syndecan-1 mRNA mostly coincided with those of syndecan-1 protein. Syndecan-1 expression was significantly lower in G-type cancers (30%) than in O- (81%) and CI-type cancers (92%) (P = 0.0001 and P = 0.004, respectively), but E-cadherin did not show this result. In addition, syndecan-1 expression was significantly reduced in DGCs comprised partly of poorly differentiated adenocarcinoma or signet-ring cell carcinoma, compared to DGCs demonstrating papillary and/or tubular adenocarcinoma (P = 0.02). G-type intestinal metaplasia (IM) surrounding the tumors was observed in 21% of G-type cancers, in 0% of O-, and in 10% of CI-type cancers (P = 0.01; G-type vs O-type). Reduction of syndecan-1 expression was significant in G-type IM (25%) compared to non-G-type IM (75%; P = 0.02).Conclusions Syndecan-1 plays a role in the growth of G-type cancers at an early stage compared with E-cadherin changes, and the reduction of syndecan-1 expression in IM surrounding the tumors may influence the growth of G-type cancer.     

Effects of Helicobacter pylori infection on mucin expression in gastric carcinoma and pericancerous tissues

BACKGROUND: Helicobacter pylori infection is one of the major causes of human gastric carcinoma and can disturb the gastric mucosa barrier. Mucins have not only lubricating and protecting functions, but are also related to signal transduction, turnover of gastric epithelium and carcinogenesis of gastric mucosa. The aim of this study was to investigate the relationship between H. pylori infection and aberrant mucin expression in patients with gastric carcinoma. METHODS: H. pylori infection was diagnosed by the Warthin-Starry staining method. Different kinds of mucins were detected using an immunohistochemical method. RESULTS: Of 46 patients with gastric carcinoma, there were 26 patients who had H. pylori infection (56.5%). Of 21 pericancerous mucosas from the H. pylori-positive patients, 14 had MUC2 expression (66.7%), seven had strong MUC1 expression (+ + +) (33.7%), seven had strong MUC6 expression (+ + +) (33.3%), and five had strong MUC5AC expression (+ + +) (23.8%). In contrast, only six of 18 H. pylori-negative pericancerous mucosas had MUC2 expression (33.3%) (P < 0.05 compared with H. pylori-positive pericancerous mucosas), 12 had strong MUC1 expression (+ + +) in 16 H. pylori-negative pericancerous mucosas (75%) (P < 0.05), 11 had strong MUC6 expression (+ + +) in 16 H. pylori-negative pericancerous mucosas (68.8%) (P < 0.05), and 10 had strong MUC5AC expression (+ + +) in 14 H. pylori-negative pericancerous mucosas (71.4%) (P < 0.01). Of the H. pylori-positive cancerous tissues, 50% (13/26) had MUC1 expression and 38.5% (10/26) had MUC6 expression. In comparison, of the H. pylori-negative cancerous tissues, 80% (16/20) had MUC1 expression (P < 0.05) and 80% (16/20) had MUC6 expression (P < 0.01). CONCLUSIONS: The results indicate that H. pylori infection can alter the expression of some mucin genes in pericancerous mucosa and cancerous tissues of gastric carcinoma, then destroy the gastric mucosa barrier.     

Prevalence of Barrett's esophagus and expression of mucin antigens detected by a panel of monoclonal antibodies in Barrett's esophagus and esophageal adenocarcinoma in Japan

Barrett's esophagus (BE) is an acquired disorder associated with a high incidence of adenocarcinoma of the lower esophagus. Moreover, it has been reported that short-segment BE may be associated with adenocarcinoma of the esophagogastric junction. The objective of this study was to define the prevalence of BE and the mucin profile in BE, including the short-segment type, and to compare the mucin profile in BE with the profiles of Barrett's adenocarcinoma and distal esophageal adenocarcinoma among Japanese. In total, 650 adult subjects underwent endoscopic examination for evaluation of BE. Although the prevalence of traditional (long segment) BE was 0.62%, the overall prevalence of BE including short-segment type was 15.7%. In Barrett's epithelium, the short-segment type predominantly had gastric type mucin, while the middle- and long-segment types possessed intestinal mucin, especially colonic type mucin (sulfo-Lewis^a), with high frequency. In Barrett's epithelium with adenocarcinoma, all Barrett's epithelium adjacent to carcinomas showed a predominance of immunoreactivity to sulfo-Lewis^a. In Barrett's adenocarcinomas, colonic type mucin was detected in 100% by monoclonal antibody (MoAb) 91.9H. Small-intestinal mucin and gastric mucin were stained in 50% and 12.5% of the subjects, respectively. Colonic type mucin was also detected with high frequency (80%) in distal esophageal adenocarcinomas without Barrett's epithelium. These data suggest that the epitope, not of small-intestinal type or gastric type mucin, but of colonic type mucin (sulfo-Lewis^a), may be associated with, at least in part, the malignant phenotype of BE. Received: July 28, 1999 / Accepted: February 25, 2000     

Primary adenocarcinoma of the cervical esophagus arising from heterotopic gastric mucosa

Received: February 18, 2000 / Accepted: November 17, 2000