A case of CA19‐9‐producing adenocarcinoma of the remnant stomach resembling gastritis cystica polyposa

Gastritis cystica polyposa (GCP) is a well‐known precancerous lesion of the remnant stomach. We report a case of carbohydrate antigen (CA) 19–9‐producing well‐differentiated adenocarcinoma of the remnant stomach that resembled GCP. The patient was a 66‐year‐old Japanese man who had undergone subtotal gastrectomy 20 years previously. The tumor developed in the remnant stomach at the anastomotic line. Histologically, the lesion completely encircled the gastroenterostomy stoma. There was florid growth of glands with cystic dilatation and minimal atypia extending through the thickened muscularis propria into the subserosa. Small foci of less well‐differentiated adenocarcinoma were also detected, including irregular glands or small clusters of mucus‐producing cells with moderate atypia. Immunostaining revealed that numerous tumor cells were positive for carcinoembryonic antigen and CA19‐9, whereas only a few cells were positive for p53. The macroscopic, histopathological and immunohistochemical findings indicated a diagnosis of CA19‐9‐producing well‐differentiated adenocarcinoma of the remnant stomach. To avoid underdiagnosis, careful attention should be paid to the above‐mentioned morphological features and immunohistochemical findings, in addition to the endoscopic findings.     

Epstein-Barr virus-associated gastric carcinoma in Kazakhstan

AIM: To investigate the incidence of Epstein-Barr virus-associated gastric cancer (EBV-GC) in Kazakhstan and to compare it with that in Russia, Western and Asian countries in order to evaluate the significance of epidemiopathologic and ethnic factors. METHODS: In situ hybridization (ISH) of EBV-encoded small RNA-1 (EBER-1) was used to identify the presence of EBER-1 signal in 139 formalin-fixed and paraffin-embedded GC tissues from Kazakhstan. RESULTS: EBER-1 expression was observed in the nuclei of 10% of the cases of GC (14/139), but not in the surrounding normal mucosa. The incidence of the diffuse type of EBV-GC was significantly higher in Kazakhstan (14%, 13/91) than that of the intestinal type (2%, 1/48). Furthermore, the incidence was significantly higher in males (14%, 12/89) than in females (3.7%, 2/53) from all countries. The overall incidence of EBV-GC increased from 6.7% in Asian countries to 8.7% in Russia, 10.1% in Kazakhstan and 16% in Western countries. CONCLUSION: Geographical differences in the incidence of EBV-GC may reflect the epidemiologic factors and/or dietary habits independent of histological type and sex.     

Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: Disease and treatments

Epstein-Barr virus(EBV)-associated gastric carcinoma(EBVaGC)comprises nearly 10%of gastric carcinoma cases worldwide.Recently,it was recognised to have unique clinicopathologic characteristics,including male predominance,lower rates of lymph node involvement,and better prognosis.EBVaGC is further characterised by abnormal hypermethylation of tumour suppressor gene promoter regions,causing down-regulation of their expression.In the present review,we critically discuss the role of EBV in gastric carcinogenesis,summarising the role of viral proteins and microRNAs with respect to aberrant methylation in EBVaGC.Given the role of epigenetic dysregulation in tumourigenesis,epigenetic modifiers may represent a novel therapeutic strategy.     

EBV感染与胃癌关系的研究进展

EB病毒(Epstein-Barr virus,EBV)是引起胃癌的重要生物学因素之一,其感染与胃癌的发生和发展密切相关.随着分子生物学技术的发展和应用,研究者对与EBV感染相关胃癌(EBVaGC)的特征和发生机制进行了深入研究,发现EBV潜伏感染和细胞恶性转化是EBV致EBVaGC的重要基础,为EBVaGC的诊断、治...     

Development of Epstein-Barr virus-associated gastric cancer: Infection,inflammation, and oncogenesis

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) cells originate from a single-cell clone infected with EBV. However, more than 95% of patients with gastric cancer have a history of Helicobacter pylori (H. pylori) infection, and H. pylori is a major causative agent of gastric cancer. Therefore, it has long been argued that H. pylori infection may affect the development of EBVaGC, a subtype of gastric cancer. Atrophic gastrointestinal inflammation, a symptom of H. pylori infection, is observed in the gastric mucosa of EBVaGC. Therefore, it remains unclear whether H. pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H. pylori and EBV infections act independently on gastric cancer formation. It has been reported that EBV infection assists in the onco-genesis of gastric cancer caused by H. pylori infection. In contrast, several studies have reported that H. pylori infection accelerates tumorigenesis initiated by EBV infection. By reviewing both clinical epidemiological and experimental data, we reorganized the role of H. pylori and EBV infections in gastric cancer formation.     

E-cadherin and beta-catenin expression in Epstein-Barr virus-associated gastric carcinoma and their prognostic significance

AIM： To examine the role of E-cadherin and betacatenin in carcinogenesis and to assess their prognostic implication in Epstein-Barr virus-associated gastric carcinomas （EBV-GCs）. METHODS： We compared the frequency of E-cadherin and beta-catenin expression in 59 EBV-GCs and 120 non-EBV-GCs, and examined the association between patients＇ prognosis and the expressions of these proteins.
RESULTS： Neither the cellular-membranous nor the cytoplasmic E-cadherin expression showed any difference between EBV-GCs and non-EBV-GCs. On the other hand, loss of membranous expression of beta- catenin occurred more frequently in non-EBV-GCs than EBV-GCs [odds ratio = 0.41; 950 confidence interval （CI）, 0.19-0.90]. Furthermore, the nuclear and/or cytoplosmic expression of beta-catenin was seen more frequently in EBV-GCs than non-EBV-GCs （odds ratio = 2.23; 95% CI, 0.97-5.09）, and was observed in a larger proportion of carcinoma cells of EBV-GCs than non-EBV-GCs （P = 0.024）. Survival analysis for non-EBV-GC revealed that lymph node metastasis was significantly associated with poor prognosis （P 〈 0.001）. Among EBV- GCs, the depth of invasion （P = 0.005）, lymph node metastasis （P = 0.004） and an intestinal type by Lauren classification （hazard ratio = 9.47; 95% CI, 2.67-33.6） were significantly associated with poor prognosis. On the other hand, nuclear and/or cytoplasmic expression of beta-catenin was associated with a better prognosis in patients with EBV-GC （hazard ratio = 0.32; 95% CI, 0.11-0.93）. CONCLUSION： We observed more frequent preservation of beta-catenin in cell membrane and accumulation in nuclei and/or cytoplasm in EBV-GCs than in non-EBV- GCs. Factors involved in the prognosis of EBV-GCs and non-EBV-GCs are different in the two conditions.     

CASE REPORT: Hypoechoic submucosal nodules: A sign of Epstein-Barr virus-associated early gastric cancer

The Epstein-Barr virus (EBV) has been reported to be detectable in about 10% of gastric carcinomas. We performed a comparative study of endosonographic findings of EBV-positive and -negative early gastric carcinomas. Epstein-Barr virus was detected in 11.8% (four of 34) of endosonographically observed early gastric carcinoma lesions. Endoscopic ultrasonography (EUS) revealed a hypoechoic mass in the third layer, which reflected submucosal nodules, in 75% (three of four) of EBV-associated lesions. Endoscopically, in 66.7% (two of three) of EBV-associated carcinomas, the depressed lesion was surrounded by a raised margin covered with normal mucosa and was similar to a submucosal tumour ( P < 0.05). Histologically, all three cases of EBV-associated lesions with submucosai tumour invasion had submucosal nodules of carcinoma with lymphoid stroma and 75% (three of four) were located in the gastric body. The ratio of maximal thickness to width of EBV-associated lesions was significantly larger than that of EBV-negative lesions, and this tendency was marked in lesions with submucosal rumour invasion ( P < 0.05). This study indicated that EUS and endoscopy are of great use for the determination of EBV association with early gastric carcinoma.     

Epstein-Barr virus-associated lymphoepithelioma-like early gastric carcinomas and endoscopic submucosal dissection: Case series

Epstein-Barr virus(EBV)-associated lymphoepitheliomalike gastric carcinoma(LELC) is characterized by a lower lymph node(LN) metastasis rate and a higher survival rate than other forms of gastric cancer. Although current prognosis for LELC is favorable, the most common approach is radical gastrectomy involving an extensive D2 lymph node dissection. Here, we report four cases of EBV-associated early LELC that were treated by an alternative approach, endoscopic submucosal dissection(ESD). The long-term outcome of this procedure is discussed. All patients were treated by ESD en bloc, and all ESD specimens showed tumor-free lateral resection margins. None of the lesions showed lymphovascular invasion. A pathological examination of ESD specimens revealed submucosal invasion of more than 500 μm in all four cases. One patient underwent additional radical surgery post-ESD; no residual tumor or LN metastasis was noted in the surgical specimen. The other three patients did not undergo additional surgery, either because of severe comorbidity or their refusal to undergo operation, but were subjected to medical follow-up. None of the ESD-treated patients reported local recurrence or distant metastases during the 27-32 mo of follow-up after ESD.     

Epstein-Barr virus-associated gastric carcinoma： Evidence of age-dependence among a Mexican population

AIM: To investigate features of Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) among a Mexican population. METHODS: Cases of primary gastric adenocarcinoma were retrieved from the files of the Departments of Pathology at the Instituto Nacional de Cancerologia and the Instituto Nacional de la Nutricion in Mexico City. The anatomic site of the gastric neoplasia was identified, and carcinomas were histologically classified as intestinal and diffuse types and subclassified as proposed by the Japanese Research Society for Gastric Cancer. EBV-encoded small non-polyadenylated RNA-1 (EBER-1) in situ hybridization was conducted to determine the presence of EBV in neoplastic cells. RESULTS: We studied 330 consecutive, non-selected, primary gastric carcinomas. Among these, there were 173 male and 157 female patients (male/female ratio 1.1/1). EBER-1 was detected in 24 (7.3%) cases (male/female ratio: 1.2/1). The mean age for the entire group was 58.1 years (range: 20-88 years), whereas the mean age for patients harboring EBER-1-positive gastric carcinomas was 65.3 years (range: 50-84 years). Age and histological type showed statistically significant differences, when EBER-1-positive and -negative gastric carcinomas were compared. EBER-1 was detected in hyperplastic- and dysplastic-gastric mucosa surrounding two EBER-1-negative carcinomas, respectively. CONCLUSION: Among Latin-American countries, Mexico has the lowest frequency of EBVaGC. Indeed, the Mexican population >50 years of age was selectively affected. Ethnic variations are responsible for the epidemiologic behavior of EBVaGC among the worldwide population.     

Phenotype analysis by MUC2, MUC5AC, MUC6, and CD10 expression in Epstein-Barr virus-associated gastric carcinoma

Background Gastric marker mucins (MUC5AC and MUC6) and intestinal marker molecules (MUC2 and CD10) have been used to determine the cell lineage of epithelial cell of gastric carcinoma (GC). Methods To clarify the characteristics of Epstein-Barr virus (EBV)-associated GC, 18 cases were immunohistochemically evaluated along with 56 cases of EBV-negative GC. Results MUC2 expression was lower in EBV-associated GC: immunostaining grades 0, 1, 2, 3, and 4 were observed in 10, 6, 1, 1, and 0 cases of EBV-associated GC, respectively, and in 18, 11, 15, 6, and 6 cases of EBV-negative GC, respectively (P = 0.013). CD10 positivity (grades 2–4) in EBV-associated GC was 6%, significantly lower than in EBV-negative GC (34%) (P = 0.030). When phenotypes of GC were categorized by the combined positivities of gastric markers (either MUC5AC or MUC6) and intestinal markers (either MUC2 or CD10), EBV-associated GC included primarily null (44%) and gastric (39%) types, but EBV-negative GC comprised null (7%), gastric (30%), intestinal (27%), and mixed (36%) types. The age of patients with gastric types was significantly younger for both EBV-associated GC and EBV-negative GC cases. Conclusions Neoplastic epithelial cells of EBV-associated GC did not express MUC2 or CD10, and most of them were categorized as null or gastric types. EBV infection may occur in the epithelial cells of null or gastric phenotypes, which may be devoid of transdifferentiation potential toward intestinal phenotypes.     

Intestinal-type tumour in resected gastric remnant cancer

Lauren's intestinal type of gastric cancer was proposed to be dependent on long-term environmental factors and is always preceded by chronic premalignant change. A cohort study was performed and demonstrated an increased cancer risk of gastric remnant after gastric surgery for benign disease. It is generally believed that after gastrectomy the residual stomach has an environmental change and, thus, enters a neoplastic process. Based on the carcinogenic theory of intestinal-type tumour, it would be of interest to know whether the intestinal-type tumour is more common in gastric remnant cancer. Forty patients with gastric remnant cancer had gastrectomy in the Veterans General Hospital-Taipei. Another 683 patients with primary gastric carcinoma underwent resection and were used as controls. The clinical characteristics, tumour stage and intestinal-type tumour were analysed in gastric remnant cancer and were compared with the various portions of primary gastric carcinoma. Although the overall distribution of intestinal-type carcinoma in gastric remnant (45%) was no different to that of any other portion of stomach cancer, intestinal-type carcinoma was more common in the early stage of gastric remnant (73%) and distal stomach (73%), but not in the proximal stomach (50%), which was supposed to have the same characteristics as the gastric remnant because of identical anatomic location. More than expected, intestinal-type carcinoma in early gastric remnant cancer together with a long incubation interval between primary surgery and later tumour occurrence were compatible with the theory of carcinogenesis of intestinal-type carcinoma.     

Enteroliths developed in a chronically obstructed afferent loop coexisting with gastric remnant carcinoma: Case report and review of the literature

A case of gastric remnant carcinoma coexisting with a chronic afferent loop syndrome harboring multiple enteroliths in a grossly dilated and elongated afferent loop is presented herein. The patient had undergone a Polya type antecolic Billroth II reconstruction for a stenosing duodenal ulcer 40 years previously. A concise review of the relevant literature is also presented.     

Epstein-Barr virus association is rare in esophageal squamous cell carcinoma

Background. A critical role of Epstein-Barr virus (EBV) in carcinogenesis of nasopharyngeal squamous cell carcinoma and gastric adenocarcinoma is strongly suspected. We analyzed the possible EBV association for Japanese squamous cell carcinoma (SCC)-dominant esophageal cancer cases. Methods. We retrospectively screened 36 surgically resected esophageal cancer lesions from 36 patients maily with SCC using in situ hybridization (ISH) for EBV-encoded small RNA1 (EBER-1). EBV DNA analysis using real-time quantitative polymerase chain reaction (Q-PCR) was performed for three recent cases. Results. We found no EBER-1-positive cancer cell in any tested esophageal cancer lesion. There were many EBER-1-positive tumor-infiltrating lymphocytes in the basaloid SCC lesion and a small number of positive lymphocytes in the other five advanced SCC lesions (14.7% of SCC). One SCC lesion with a highcopy number of EBV DNA had EBER-1-positive lymphocytes. Conclusions. EBV is rarely associated with esophageal SCC, and may appear through tumor-infiltrating lymphocytes in some advanced lesions.     

Clinical impact of Epstein-Barr virus status on the incidence of lymph node metastasis in early gastric cancer

Epstein-Barr virus-positive gastric cancer (EBVGC) comprises approximately 9% of all gastric cancers and is associated with a low prevalence of lymph node metastasis (LNM). Given that limited data concerning LNM in EBV-related early GC are available, EBV status is not considered an indicator for endoscopic submucosal dissection (ESD). In this review, we focused on pT1 EBVGC and on gastric carcinoma with lymphoid stroma (GCLS), and discuss expanded ESD indications and curative resection criteria. In pT1b EBVGC, the incidence of LNM was low (6/180 patients, 3.3%; 95% confidence interval [CI] 1.2–7.1), especially in lymphovascular invasion-negative EBVGC (1/109 patients, 0.9%). No patients with pT1a EBVGC had LNM (0/38 patients, 0%; 95% CI 0–7.6), even those who did not meet the current curative ESD criteria. Although the frequency of LNM in GCLS was low (5.0–10.6%), the incidence of LNM in non-EBV GCLS was relatively high (10.0–20.0%); therefore, EBV status can be considered a more important factor than GCLS. In summary, the clinicopathological characteristics of EBVGC differ from those of conventional GC, and EBV negativity is a risk factor for LNM in early GC. Therefore, patients in this group are likely to be promising candidates for ESD, and we recommend that EBV status evaluation be included in early GC treatment guidelines.     

Evidence of Epstein-Barr Virus Association with Gastric Cancer and Non-Atrophic Gastritis

Different lines of evidence support an association between Epstein-Barr virus (EBV) and gastric cancer (GC). The main understood risk factor to develop GC is infection by Helicobacter pylori (H. pylori), which triggers a local inflammatory response critical for progression from gastritis to GC. The role of EBV in early inflammatory gastric lesions has been poorly studied. A recent study proposed a cutoff value of 2000 EBV particles to identify patients with increased chances of infection of the gastric epithelium, which may favor the inflammatory process. To better understand the role of EBV in cancer progression, we analyzed 75 samples of GC, 147 control samples of non-tumor gastric tissue derived from GC patients and 75 biopsies from patients with non-atrophic gastritis (NAG). A first-round PCR was used for EBV detection in tumor and non-tumor controls and a more sensitive nested PCR for gastritis samples; both PCRs had lower detection limits above the proposed cutoff value. With this strategy 10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples. Our results support a role for EBV in GC and early precursor lesions, either as directly oncogenic infecting epithelial cells or indirectly as an inflammatory trigger.     

Total pancreatectomy for metachronous mixed acinar-ductal carcinoma in a remnant pancreas

In October 2009, a 71-year-old female was diagnosed with a cystic tumor in the tail of the pancreas with an irregular dilatation of the main pancreatic duct in the body and tail of the pancreas. A distal pancreatectomy with splenectomy, and partial resection of the duodenum, jejunum and transverse colon was performed. In March 2011, a follow-up computed tomography scan showed a low density mass at the head of the remnant pancreas. We diagnosed it as a recurrence of the tumor and performed a total pancreatectomy for the remnant pancreas. In the histological evaluation of the resected specimen of the distal pancreas, the neoplastic cells formed an acinar and papillary structure that extended into the main pancreatic duct. Mucin5AC, α1-antitrypsin (α-AT) and carcinoembryonic antigen (CEA) were detected in the tumor cells by immunohistochemistry. In the resected head of the pancreas, the tumor was composed of both acinar and ductal elements with a mottled pattern. The proportions of each element were approximately 40% and 60%, respectively. Strongly positive α-AT cells were detected in the acinar element. Some tumor cells were also CEA positive. However, the staining for synaptophysin and chromogranin A was negative in the tumor cells. Ultimately, we diagnosed the tumor as a recurrence of mixed acinar-ductal carcinoma in the remnant pancreas. In conclusion, we report here a rare case of repeated pancreatic resection for multicentric lesions of mixed acinar-ductal carcinoma of the pancreas.     

Lymphoepithelioma-like gastric carcinoma: A case report and review of the literature

Lymphoepithelioma-like gastric carcinoma is a rare type of gastric cancer characterized by a carcinoma with intense stromal lymphocytic infiltration. Although lymphocytic infiltration is closely associated with EpsteinBarr virus(EBV) infection, concomitant occurrence with differentiated adenocarcinoma is relatively rare. The clinical manifestations of lymphoepithelioma-like gastric carcinoma(including EBV-positive and-negative forms) are similar to those of gastric cancer, and the diagnosis is based on pathologic, histologic, and immunohistochemical findings. This report describes the case of a 55-year-old female patient who presented with a 10-year history of recurrent and worsening abdominal pain and melena that had been occurring for 2 mo. An ulcerative lesion was detected in the stomach by endoscopic examination, which raised suspicion of early gastric cancer. A subsequent preoperative endoscopic biopsy showed adenocarcinoma, but the postoperative pathologic, histologic, and immunohistochemical analyses of the resected specimen revealed a final diagnosis of lymphoepithelioma-like gastric carcinoma.