Immunohistochemical study of neuroendocrine cells at the gastric cardia mucosa

BACKGROUND/AIMS: The gastric cardia mucosa is a narrow band of tissue between the oesophagus and the stomach. The physiological role of this tissue is unknown. This study examined the presence and characteristics of neuroendocrine cells at this site. METHODS: Biopsy samples were obtained from across normal appearing squamocolumnar junctions. The cardiac mucosa was defined as the presence of special type mucosa composed of mucous secreting glands in the immediate vicinity of oesophageal squamous epithelium. Biopsy specimens were stained with haematoxylin and eosin, alcian blue (pH 2.5) periodic acid Schiff, and modified Giemsa. The chromogranin A and Fontana-Masson stains were used to identify neuroendocrine cells, which were also stained immunohistochemically for gastrin, serotonin, glucagon, pancreatic polypeptide, somatostatin, and vasoactive intestinal peptide. RESULTS: Chromogranin positive cells were seen in 18 cases with adequate biopsy specimens from the gastric cardia mucosa. These cells were all serotonin positive, but stains for other peptide hormones remained negative. Serotonin positive cells were detected only at the base of foveolae at the periphery of mucous secreting cardiac glands, giving a microscopic appearance resembling that of endocrine cells at the gastric antrum. The presence and numbers of serotonin positive cells did not correlate with chronic inflammation or intestinal metaplasia of the cardiac mucosa. These cells were seen both in Helicobacter pylori positive and negative patients. CONCLUSIONS: Serotonin positive cells appear to be the sole neuroendocrine cell type at the gastric cardia mucosa. These cells may have a role in regulating the physiology of the gastric cardia mucosa and the lower oesophageal sphincter.     

Collision carcinoma of the gastric cardia

A case of squamous cell carcinoma of the lower end of the esophagus colliding with adenocarcinoma of the cardiac end of the stomach is reported. The rarity of the lesion, its diagnostic criteria, and therapeutic implications are briefly discussed.     

Parietal cell carcinoma of gastric cardia: immunophenotype and ultrastructure

The case is reported of a clinically aggressive parietal cell carcinoma of the gastric cardia in a 67-year-old man. Histologically, the tumor was a poorly differentiated adenocarcinoma with a predominantly solid growth pattern, though with areas exhibiting glandular morphology and with extensive lymphatic invasion. The tumor cells had eosinophilic, finely granular cytoplasm, with focal Alcian blue-positive mucin in the gland lumens. Ultrastructural examination of the pleural metastasis and gastrectomy specimen demonstrated many mitochondria, tubulovesicular profiles of endoplasmic reticulum, and intracytoplasmic lumens, which resembled intracellular canaliculi of parietal cells. Immunohistochemically, there was positive staining of tumor cells for the parietal cell specific antibodies to H/K-ATPase and human milk fat globule-2 (HMFG-2).     

Cancer of the gastric cardia and the habit of smoking

The habits of smoking and drinking were investigated in relation to pathologic findings in the stomachs of 1,347 patients who had undergone surgery for gastric cancer at Toranomon Hospital between 1977 and 1986. There were 1,210 patients (807 males and 403 females) with single gastric cancer and 137 (117 males and 20 females) with multiple gastric cancer. The most frequent location of the tumor in cases of single gastric cancer was the middle third (47.8%), followed by the distal third (33.4%), upper third (13.1%) and cardiac region (5.7%). Tobacco consumption was positively associated with gastric cancer in males (odds ratio as the approximate relative risk = 2.8), whereas alcohol consumption was not. Neither tobacco nor alcohol consumption was positively associated with gastric cancer in females. Among male patients with single cancer, the habit of smoking was more prevalent in those with cancer of the cardia than in those with cancer of other portions of the stomach (p less than 0.01).     

A positive family history of esophageal/gastric cardia cancer with gastric cardia adenocarcinoma is associated with a younger age at onset and more likely with another synchronous esophageal/gastric cardia cancer in a Chinese high-risk area

BackgroundTo find a genetic component in gastric cardia adenocarcinomas (GCA).MethodsAge at onset (AO) and rate of another synchronous primary upper gastrointestinal carcinoma (RASPUGIC) were compared among the three GCA groups with positive (N = 766), negative (N = 2167), and missing family history of upper gastrointestinal cancer (FHUGIC) (N = 198). These 3131 GCAs were diagnosed on 3128 primary GCA patients of a consecutive surgical cohort treated from 1973 through 1994 at the Department of Thoracic Surgery in the 4th Hospital of Hebei Medical University in a high-risk region in northern China.ResultsOverall, GCAs of positive FHUGIC showed a significantly younger AO and a significantly higher RASPUGIC than the negative group (54.68 ± 7.35 vs 55.94 ± 7.47 years old, Pt-test = 0.000; 3.1% vs 1.3%, χ2 = 11.02, P = 0.001). The difference in AO and RASPUGIC between the positive and the negative FHUGIC GCAs is significant or nearly significant in most subgroups; minimizing the possibility of a false association due to bias or confounding (e.g. significant stage-specific differences in AO between familial and sporadic GCAs observed in the subgroup of T2,3N0M0 (P = 0.000) and T2,3,4N1M0 (P = 0.03) exclude the possibility of ascertainment bias towards an earlier diagnosis in familial cases), and the association between FHUGIC and RASPUGIC is statistically significant for GCAs of younger AO (<55 yr old, RASPUGIC 3.8% vs 1.6% vs 1.1% for the positive, negative and missing FHUGIC GCAs respectively, χ2 = 6.50, P = 0.04), but not significant for the later onset GCAs (≥55 yr old, RASPUGIC 2.5%, 1.1%, 1.9% for the positive, negative and missing FHUGIC respectively, χ2 = 4.22, P = 0.12).ConclusionThese findings suggest a genetic component in GCA in the Chinese high-risk region, and genetic predisposition may determine the age at onset and number of primary upper gastrointestinal cancer.     

Gastric cardia inflammation and intestinal metaplasia: associations with reflux esophagitis and Helicobacter pylori.

Gastric cardia inflammation and intestinal metaplasia are the subjects of recent investigation. Some authors have found associations with gastroesophageal reflux disease, whereas others have identified relationships with Helicobacter pylori (HP). We studied 150 consecutive patients who underwent upper endoscopy, had normal gastroesophageal anatomy, and had biopsies of the antrum, cardia, and lower esophagus, to evaluate relationships between reflux esophagitis, cardia inflammation, intestinal metaplasia, and HP gastritis. Forty-two patients had HP infection. Cardia inflammation was significantly related to esophageal squamous inflammation in the non-HP-infected patient group and to antral inflammation and cardia HP infection in the HP-infected patient group. The differences between the patient groups was most apparent in the patients with moderate or marked inflammation. Twenty-seven percent of patients had cardia intestinal metaplasia that was related to cardia inflammation. Cardia inflammation and intestinal metaplasia probably have multiple causes. Pathologists should refrain from applying the term Barrett's esophagus for biopsies procured from the cardia that show intestinal metaplasia in patients with a normal squamocolumnar junction.     

Lymphatic anastomoses between the distal esophagus and gastric cardia in dogs

The intramural lymphatic system draining the distal esophagus and gastric cardia was studied on 35 mongrel dogs, using a dye injection procedure. When the dye was injected into the esophageal or gastric mucosa within 2 cm of the esophago-gastric junction (EGJ), a mesh of lympho-capillary networks was observed advancing inferiorly or superiorly across the EGJ. The intramural lymphatics of the distal esophagus and gastric cardia anastomose, especially in the central part of the muscularis mucosae. On transmission electron microscopy, lumina filled with dye were proved to be lymphatic capillaries by demonstrating open gaps and overlapping or inter-digitating endothelial cell processes. Some lympho-capillaries containing dye were also observed beneath the esophageal epithelium. If the situation be extrapolated to human anatomy, the results suggest that lymphatic neoplastic metastases may occur even in early cases of carcinoma of the distal esophagus or gastric cardia.     

Mammary mucinous lesions: congeners, prevalence and important pathological associations

A retrospective histopathological study was undertaken to determine the prevalence of mucin filled ducts and their associated mucinous proliferation in 962 breast cancers and 335 benign lesions. A total of 38 (3%) cases with mucin filled ducts was identified and 27 (2%) of these showed mucin extravasation into the adjacent stroma, changes characteristic of mucocoele-like lesions. This constitutes the largest series reported to date. Of the mucocoele-like lesions 12 were prototypic screen-detected cases; 11 of which were mammographically detected on account of suspicious microcalcification and eight cases (67%) exhibited mucinous atypical ductal hyperplasia without overt malignancy. A further 12 mucocoele-like lesions were incidental findings in screen-detected (11) and symptomatic (one) cancers, the majority of which were invasive ductal carcinomas of no special type. In six of these cases (50%), mucinous atypical ductal hyperplasia or ductal carcinoma in situ was present. Thirty mucinous carcinomas constituted 3% of all cancers and three cases had associated mucocoele-like lesions. Mucinous atypical ductal hyperplasia or ductal carcinoma in situ was also associated with 11 cases of mucinous carcinoma. In six mucinous carcinomas, amorphous microcalcification with a similar appearance to that of benign mucocoele-like lesions was identified in the mucin, suggesting a possible link between the two lesions. Mucin-filled ducts or mucocoele-like lesions were almost twice as frequent in screen-detected as in symptomatic lesions. The presence of mucinous atypical ductal hyperplasia in screen-detected mucocoele-like lesions, a decade earlier than the peak of mucinous carcinoma, is a possible risk factor for subsequent invasive malignancy. Mucin-filled ducts, mucocoele-like lesions, mucinous atypical ductal hyperplasia or ductal carcinoma in situ and mucinous carcinoma may represent different stages of the same disease process. Our findings suggest that patients with mucin-filled ducts of mucocoele-like lesions merit close follow-up.     

胃贲门混合性腺-神经内分泌癌一例

患者男,70岁.因吞咽困难2个月,进行性加重就诊,门诊行胃镜检查示"贲门癌"于2008年11月12日收入院.行全麻下贲门癌切除,食管胃弓下吻合术,手术顺利.     

p53 abnormalities in adenocarcinoma of the gastric cardia and antrum.

AIM: To compare the frequency and type of p53 alterations (gene mutation and/or protein overexpression) in a consecutive series of surgically resected adenocarcinomas arising in the gastric cardia and gastric antrum, and to evaluate associations with clinicopathological findings (age, sex, and tumour histology, grade, and stage). METHODS: The series comprised 50 patients with adenocarcinoma of the cardia and 20 patients with adenocarcinoma of the antrum. p53 gene mutations (exons 5-8) were detected by denaturing gradient gel analysis and DNA sequencing. Nuclear p53 overexpression was detected by immunohistochemistry with the DO7 antibody. RESULTS: p53 gene mutations were found in 21 of 50 and five of 20 adenocarcinomas of the cardia and the antrum, respectively. Base transitions occurring at CpG dinucleotides were frequent in both types of tumour. p53 protein overexpression was seen in 32 of 50 and seven of 20 adenocarcinomas of the cardia and of the antrum, respectively. p53 gene mutation and/or protein overexpression were significantly more frequent in adenocarcinomas of the cardia (37 of 50) than in adenocarcinomas of the antrum (seven of 20). There were no differences in the clinicopathological characteristics of the tumours between p53 positive and p53 negative cases in both types of cancer. CONCLUSIONS: This study shows that p53 alterations are more frequent in adenocarcinoma of the cardia than in adenocarcinoma of the antrum. This feature is consistent with the clinical and epidemiological characteristics of these cancers, which suggest that adenocarcinoma arising in the gastric cardia might be related to oesophageal adenocarcinoma, and unrelated to adenocarcinomas of the gastric body and antrum.     

p53 abnormalities in adenocarcinoma of the gastric cardia and antrum.

AIM: To compare the frequency and type of p53 alterations (gene mutation and/or protein overexpression) in a consecutive series of surgically resected adenocarcinomas arising in the gastric cardia and gastric antrum, and to evaluate associations with clinicopathological findings (age, sex, and tumour histology, grade, and stage). METHODS: The series comprised 50 patients with adenocarcinoma of the cardia and 20 patients with adenocarcinoma of the antrum. p53 gene mutations (exons 5-8) were detected by denaturing gradient gel analysis and DNA sequencing. Nuclear p53 overexpression was detected by immunohistochemistry with the DO7 antibody. RESULTS: p53 gene mutations were found in 21 of 50 and five of 20 adenocarcinomas of the cardia and the antrum, respectively. Base transitions occurring at CpG dinucleotides were frequent in both types of tumour. p53 protein overexpression was seen in 32 of 50 and seven of 20 adenocarcinomas of the cardia and of the antrum, respectively. p53 gene mutation and/or protein overexpression were significantly more frequent in adenocarcinomas of the cardia (37 of 50) than in adenocarcinomas of the antrum (seven of 20). There were no differences in the clinicopathological characteristics of the tumours between p53 positive and p53 negative cases in both types of cancer. CONCLUSIONS: This study shows that p53 alterations are more frequent in adenocarcinoma of the cardia than in adenocarcinoma of the antrum. This feature is consistent with the clinical and epidemiological characteristics of these cancers, which suggest that adenocarcinoma arising in the gastric cardia might be related to oesophageal adenocarcinoma, and unrelated to adenocarcinomas of the gastric body and antrum.     

Molecular cytogenetic evaluation of gastric cardia adenocarcinoma and precursor lesions

Analyses of cancer incidence data in the United States and Western Europe revealed steadily rising rates over the past decades of adenocarcinomas of the esophagus and gastric cardia. Genetic information on gastric cardia adenocarcinoma and its preneoplasias is sparse. We have used comparative genomic hybridization to obtain a genome-wide overview of 20 archival gastric cardia adenocarcinomas and 10 adjacent preneoplastic lesions (4 metaplasias, 1 low-grade dysplasia, 5 high-grade dysplasias). Multiple genetic alterations were discriminated in all adenocarcinomas. Frequent loss (> or =25% of all tumors) was detected, in decreasing order of frequency, on 5q, 18q, 4q, 3p, 9p, 2q, 11q, 14q, 21q, 4p, 9q, 16q, 1p, and 8p. Frequent gain (> or =25% of all tumors) was disclosed, in decreasing order of frequency, on 20q, 7p, 8q, 1q, 7q, 20p, 17q, 13q, Xp, 6q, 8p, 19q, 5p, 6p, and Xq. Loss of the Y chromosome was found in 60% of male cases. High level amplification was frequently (>10% of all tumors) detected on 7q21, 8p22, 12p11.2, 17q12-q21, and 19q13.1-q13.2. The precursor lesions showed multiple aberrations in all high-grade dysplasias, whereas few genetic changes were discerned in LGD and metaplasias. High level amplifications were also found in high-grade dysplasias, ie, on 7q21, 8p22, and 17q12-q21. Moreover, the percentage of aberrations was not significantly different for invasive carcinomas or high-grade dysplasias. Approximately 70% of the precursor aberrations were also present in the adjacent carcinoma. Minimal overlapping regions in the preneoplasias included loss on 18q12-q21 and gains on 8q23 and 17q12-q21, suggesting involvement of genes residing in these regions. In conclusion, we have (i) created a map of genetic alterations in gastric cardia adenocarcinomas and (ii) provided evidence for the presence of a metaplasia-dysplasia-carcinoma sequence in this poorly understood type of cancer.     

Molecular and clinical differences between adenocarcinomas of the esophagus and of the gastric cardia

Adenocarcinoma of the esophagus (ADCE) with Barrett's mucosa and adenocarcinoma of the cardia (ADCC) are often reported as a single pathological entity. In this study we have used strict anatomical-pathological criteria to distinguish between these two lesions and we have investigated their differences in TP53 mutations, MDM2 gene amplification, and cytokeratin expression. DNA was extracted from the tumor areas of formalin-fixed, paraffin-embedded sections in 26 ADCC and 28 ADCE patients. TP53 mutations were detected by temporal temperature gradient electrophoresis and identified by sequencing. MDM2 amplification was assessed by differential polymerase chain reaction. The expression of cytokeratins 4, 7, and 13 was examined by immunohistochemistry. In ADCC, the male to female ratio was 1.8:1, compared to 27:1 in ADCE. Five ADCC patients had a history of other neoplasms, compared to only one ADCE patient. The two types of tumor differed in the prevalence of TP53 mutations (31% in ADCC and 50% in ADCE) and of MDM2 gene amplification (19% in ADCC and 4% in ADCE), and in the pattern of expression of cytokeratin 7 (positive in 100% of ADCE and in 41% of ADCC) and cytokeratin 13 (positive in 81% of ADCE and in 36.5% of ADCC). ADCE and ADCC differ in their clinical characteristics, in the prevalence of TP53 mutations and MDM2 amplifications, and in the patterns of cytokeratin expression. These results support the notion that ADCC and ADCE are distinct pathological entities.     

Extremely well-differentiated adenocarcinoma of the gastric cardia: a unique case with columnar cells and laminated stones

Extremely well-differentiated adenocarcinoma (EWDA) is an unusual gastric cancer that is histologically too bland to be diagnosed as malignant neoplasm, particularly using biopsy. EWDA may be a gastric counterpart of 'adenoma malignum' or minimal deviation adenocarcinoma (MDA) in the uterine cervix; however, the clinicopathological features of EWDA remain less apparent than those of MDA. A 60-year-old male was complaining of dysphagia. He had been made aware of a small submucosal tumor in the cardia 2 years before the onset of this symptom. Endoscopic ultrasonographic examination revealed a large cardiac tumor consisting of thickened layers, as observed in Borrmann type IV. Three mucosal biopsies suggested only benign changes including adenoma and hyperplastic polyps. At the fourth biopsy, cytologically bland columnar cells were located in the submucosa along with stromal fibrosis and laminated stones. The possibility that non-neoplastic aberrant pancreas with lithiasis formed the tumor was denied at laparotomy by a frozen section that revealed benign-looking glands invading the diaphragm. Immunohistochemically the cancer glands were positive for CA19-9 and human gastric mucin, but not for p53 or MUC2. To our knowledge, this is a previously unknown combination of EWDA and psammomatous calcification in the stomach.     

Expression of EpCam and villin in Barrett's esophagus and in gastric cardia

In the current study we aimed to clarify the potential of EpCAM and villin as in vivo biomarkers for both Barrett esophagus (BE)-associated neoplasia and BE versus cardiac mucosa. Immunohistochemical staining in BE with various degrees of intraepithelial neoplasia (IN), Barrett carcinoma (BC) and in normal cardiac mucosa (CM) revealed a lack of EpCam and villin in squamous esophageal epithelium. All specimens of IN and BC showed EpCam with varying staining intensities. In 57% of CM samples a weak signal was detected; the remainder displayed strong EpCam expression. Villin was found in 97% of BE specimens and in all those with IN; 37% of BC and 75% of CM specimens were~also positive. We conclude that expression of EpCam and villin differs only between squamous epithelium and BE. Determination of these proteins does not allow discrimination between different degrees of neoplasia or between esophageal intestinal metaplasia and cardiac mucosa.     

贲门腺癌中SFRP1、DKK3基因启动子区甲基化状态的联合分析

目的研究贲门腺癌(gastric cardia adenocarcinoma,GCA)中Wnt通路拮抗基因分泌型卷曲相关蛋白1(SFRP1)和DKK3(Dickkopf3)基因的甲基化状态,探讨其与贲门腺癌发生的关系。方法应用甲基化特异性PCR(MSP)法检测89例贲门腺癌及相应正常黏膜组织中SFRP1和DKK3基因的甲基化状态,并分析与临床病理参数间的关系。结果89例贲门腺癌组织中SFRP1和DKK3基因发生甲基化的分别有77例(86.5%)和16例(20.0%),而正常黏膜组织中仅有15例(13.9%)发生了SFRP1基因的甲基化,未发现有DKK3基因的甲基化现象,癌组织中两基因的甲基化率均明显高于正常黏膜组织(P0.05);SFRP1基因的高甲基化与肿瘤组织的淋巴结转移相关,而与肿瘤的浸润深度、临床分期及病理分级无关,DKK3基因的甲基化与各临床病理指标均无关(P0.05);联合分析SFRP1和DKK3基因,在贲门腺癌组织中两基因共同发生甲基化的有12例,其共同甲基化率与肿瘤的淋巴结转移及TNM分期相关(P0.05)。结论贲门腺癌中SFRP1和DKK3基因的高甲基化状态可能是引起贲门腺癌发生的分子机制之一;SFRP1、DKK3基因甲基化的联合检测对于贲门腺癌的预后评估有一定的参考价值。     

p53基因突变与食管贲门多源癌的相关性

目的 探讨食管贲门双源癌组织p53基因突变的特征及其与p53蛋白表达的关系。方法 采用显微切割、PCR、DNA测序和免疫组化ABC法，分析4例食管贲门多源癌p53基因突变和蛋白表达状况。结果 4例食管贲门双源癌中，1例食管鳞癌和贲门腺癌同时发生p53基因突变，并均发生第7外显子231、232密码子的点突变和225、232～233、234密码子的缺失/插入改变。食管鳞癌p53基因突变率为50％(2／4)，贲门腺癌为75％(3／4)。所有检测到的突变均发生在第7和8外显子。食管癌和贲门癌分别有1例p53蛋白阴性表达的患者检测到p53基因突变，食管癌中1例p53蛋白阳性表达患者未检测到基因突变。结论 同一个体食管鳞癌和贲门腺癌组织同时发生相似位点的p53基因突变，提示二者具有相似的发病因素和分子机制，为进一步揭示林州地区相似的食管／贲门癌区域分布特征提供了重要的理论依据和线索。