Conventional Gastric Adenocarcinoma Research Articles

Mutational Landscape of Gastric Adenocarcinoma of the Fundic Gland Type Revealed by Whole Genome Sequencing.

Gastric adenocarcinoma of the fundic gland type (GA-FG) is a newly described variant of gastric adenocarcinoma with lack of knowledges regarding its genetic features. We performed whole-genome sequencing (WGS) in formalin-fixed paraffin-embedded (FFPE) tumor tissues and matched adjacent noncancerous specimens from 21 patients with GA-FG, and integrated published datasets from 1105 patients with traditional gastric adenocarcinoma with the purpose of dissecting genetic determinants both common to conventional gastric adenocarcinoma and unique to GA-FG disease. We characterized the genomic architecture of GA-FG disease, revealing the predominant proportion of C > T substitution among the six types of SNVs. GNAS was the most significantly mutated driver gene (14.29%). 42.8% of samples harbored "Kataegis." Distinct genomic alterations between GA-FG and conventional gastric cancer were identified. Specifically, low mutational burden and relatively moderate mutational frequencies of significantly mutated driver genes, coupled with the absence of non-silent alterations of formerly well-known drivers such as TP53, PIK3CA and KRAS were identified in GA-FG patients. Oncogenic signaling pathway analysis revealed mutational processes associated with focal adhesions and proteoglycans in cancer, highlighting both common and specific procedures during the development of GA-FG and conventional gastric cancer. Our study is the first to comprehensively depict the genomic landscape highlighting the multidimensional perturbations in GA-FG patients. These discoveries offered mechanistic insights for novel diagnostic and therapeutic strategies for patients with such disease.

Comparison of Prognosis and Metachronous Gastric Tumor Rates After Endoscopic Submucosal Dissection Between Gastric Neoplasm of Fundic Gland Type Neoplasms and Conventional Gastric Adenocarcinoma.

Gastric neoplasm of the fundic gland type (GNFG) is a tumor with a good prognosis. However, since it has not been compared with conventional gastric adenocarcinoma (CGA), it is unknown whether it has a good prognosis or requires surveillance after treatment. The purpose of this study was to determine the prognosis and metachronous gastric tumor rates compared with those of CGA. We conducted a single-center, retrospective, matched-cohort study using our database from January 2010 to December 2021. We extracted GNFG data from the endoscopic submucosal dissection (ESD) database and matched patients with conventional early gastric cancer as controls in a 1:4 ratio by age and sex. GNFG and CGA were compared for the overall survival (OS), disease-specific survival, progression-free survival, and metachronous gastric tumor rates. Overall, 43 lesions were GNFG and 164 CGAs were matched. There were three deaths in the GNFG group and 11 deaths in the CGA group. There was no significant difference in the OS between the two groups (P=0.81). The five-year OS rates for the GNFG and CGA groups were 90.9% and 92.9%, respectively. No disease-specific deaths or recurrences were observed in either group. There was no significant difference in the cumulative metachronous gastric tumor rate between the two groups (P=0.17). The cumulative five-year metachronous gastric tumor rates for the GNFG and CGA groups were 6.6% and 2.5%, respectively. The prognosis for GNFG is good, however, not better than that for CGA. The metachronous gastric tumor rate after ESD in GNFG was not lower than that in CGA. Therefore, after ESD, GNFGmay need to be managed in the same way as CGA.

Gastric Cancer Showing Rapid Recurrence and Progression: A Case of Gastric Adenocarcinoma With Enteroblastic Differentiation

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is rare and its clinicopathological characteristics are not well documented. However, reports indicate that it exhibits more aggressive characteristics, including lymph node metastasis or liver metastasis, than a conventional gastric adenocarcinoma. Herein, we report a case of GAED with rapid recurrence and disease progression. A 55-year-old male, diagnosed with gastric cancer (GC), demonstrated initial endoscopic findings suggestive of advanced GC. He underwent curative resection since there was no evidence of lymph node or distant metastases. The disease was reported as an early GC that was confined to the submucosal layer, without evidence of lymph node metastasis in the final pathological results. However, six months after surgery, multiple hepatic metastases were found during abdominal computed tomography; the pathological results were consistent with metastasis from the GC. Immunohistochemistry of the primary carcinoma pathological specimens showed positive results for alpha-fetoprotein and sal-like protein 4, suggesting enteroblastic differentiation, which is thought to be associated with rapid recurrence and disease progression.

Gastric adenocarcinoma with intestinal progenitor cell differentiation: a morphologically underdiagnosed and more invasive distinctive type of gastric adenocarcinoma.

This study aims to explore the clinical and pathological characteristics, prognosis, diagnosis, and differential diagnosis of gastric adenocarcinoma with enteroblastic differentiation (GAED) in elderly patients. A total of 16 cases of GAED diagnosed from August 2019 to August 2022 at the First Affiliated Hospital of Nanchang University were retrospectively collected to analyze their clinical and pathological features. A control group of 360 cases of conventional gastric adenocarcinoma diagnosed during the same period was used for comparison. Among the 16 GAED patients, 11 were male and 5 were female, with ages ranging from 64 to 89 years (median age 75.5 years). Clinical manifestations of these patients included symptoms such as abdominal pain, bloating, hematemesis, and melena. The macroscopic classification revealed 11 cases of ulcerative lesions, 4 protruded lesions, and 1 diffusely infiltrative lesion. Tumor sizes varied from 3 to 9.5 cm in diameter, with a median diameter of 4.75 cm. Microscopically, the tumor cells exhibited tubular, papillary, and cribriform arrangements, with cuboidal or columnar morphology, relatively distinct cell boundaries, and cytoplasm that appeared clear or weakly acidophilic. Immunophenotyping analysis revealed the expression of SALL4 (15/16), Glypican-3 (12/16), CDX2 (12/16), CD10 (10/16), and p53 (12 cases exhibiting mutant expression, 4 cases exhibiting wild-type expression) within the tumor cells. There was no loss of mismatch repair proteins (MLH1, PMS2, MSH2, MSH6). The Ki-67 proliferation index ranged from 50% to 95%. In comparison to conventional gastric adenocarcinoma, GAED was frequently found in the gastric antrum (P<0.001) and exhibited a higher incidence of intravascular cancer emboli (P<0.001). Significant differences were noted in the Lauren classification, invasion depth, differentiation degree (P<0.01), and macroscopic type (P<0.05). However, no significant differences were found regarding age, gender, tumor diameter, neural invasion, or lymph node metastasis (P>0.05). The postoperative follow-up ranging from 5 to 29 months revealed one death and 15 cases of disease-free survival. GAED is a special subtype of gastric adenocarcinoma characterized by a combination of embryonal and intestinal differentiation immunophenotypes, as well as its increased propensity for biological invasion. Accurate identification of GAED is crucial in pathological practice, as it helps differentiate between GAED and conventional adenocarcinoma and aids in the evaluation of tumor malignancy. Furthermore, it is imperative to conduct a differential diagnosis that involves hepatoid adenocarcinoma, yolk sac tumor-like adenocarcinoma, and metastatic hepatocellular carcinoma.

Clinicopathological characteristics of gastric adenocarcinoma with enteroblastic differentiation and gastric adenocarcinoma with enteroblastic marker expression.

Gastric adenocarcinoma (GA) with enteroblastic differentiation (GAED) is an aggressive carcinoma histologically characterized by a glycogen-rich clear cytoplasm and fetal gut-like structures. GAED shows the expression of at least one of the following enteroblastic markers (EMs): glypican-3 (GPC3), spalt-like transcription factor 4 (SALL4), and α-fetoprotein (AFP). Despite the absence of clear cytoplasm, we often encounter GA with EMs expression (GA with EM); however, the clinicopathological characteristics of GA with EM remain unclear. Immunohistochemical (IHC) expression of three EMs (AFP, GPC3, and SALL4) was examined on tissue microarray. According to the status of the clear cytoplasm of tumor cells, GAs showing IHC expression of EMs were classified as either GAED or GA with EM, and this analysis categorized 688 GAs into 94 GAEDs (13.7%), 58 GAs with EM (8.4%), and 536 conventional GAs (CGAs). Both GAED and GA with EM showed frequent lymphovascular invasion, lymph node metastasis, and liver metastasis compared to CGA. However, a higher frequency of venous invasion, but not of lymphatic invasion, was noted for GAED in comparison to CGA. GAED and GA with EM showed similar overall survival. GAED had significantly poorer prognosis than CGA; however, not for GA with EM. Furthermore, GA showing EM expression had a worse prognosis than CGA. Interestingly, GA showing EM-positive group was more aggressive than CGA group as they had frequent venous invasion and liver metastasis despite its smaller tumor size. GAED and GA with EM can be clinically classified as aggressive tumors but pathologically they seem to be slightly different.

Clinicopathological and molecular characteristics of the alpha-fetoprotein-producing gastric cancer: emphasis on two major subtypes.

Alpha-fetoprotein-producing gastric cancer (AFPGC) is associated with high invasion and poor prognosis, but has not been well-documented due to its rarity. To develop the understanding of AFPGC, and further facilitate its clinical decision-making and treatment, we performed clinicopathological and molecular characterization of AFPGC and its two major subtypes, namely, gastric adenocarcinoma with enteroblastic differentiation (GAED) and hepatoid adenocarcinoma (HAC). The clinicopathological and molecular characteristics of AFPGC patients (n = 54) were mainly investigated by immunohistochemistry and next-generation sequencing (NGS) approaches. AFPGC exhibited a higher incidence of lymphatic and vascular invasion than conventional gastric adenocarcinoma (CGA). Despite various morphological patterns, there was mostly no evident difference in clinicopathological characteristics between the GAED and HAC subtypes. Target-enriched NGS profiling of disease mutation landscapes discovered 17 differentially mutated genes between AFPGC and CGA. The AFPGC patients carrying ZNF217 mutations had poorer overall survival than the ZNF217 wildtype. Furthermore, ATR showed a significantly higher mutation rate in GAED than in HAC. Overall, our study of clinicopathological characteristics shed light on the differences between CGA and AFPGC, as well as the relationships between the GAED and HAC subtypes of AFPGC. Furthermore, mutation landscape profiling revealed potential diagnostic and prognostic markers for AFPGC and its two subtypes.

Epstein–Barr Virus Positive Gastric Cancer: A Distinct Subtype Candidate for Immunotherapy

BackgroundEpstein–Barr virus (EBV) positive gastric cancer (GC) has been described as a distinct molecular subtype of the disease, especially associated with gastric carcinoma with lymphoid stroma (GCLS). The possibility that EBV associated GC (EBVaGC) had better prognosis and may be susceptible to immunotherapy has increased the interest in this subtype. However, immune checkpoint and survival of EBVaGC are still controversial, especially with regard to GCLS and conventional gastric adenocarcinoma (CGA). This study aimed to evaluate the clinicopathological characteristics, immunohistochemical profiles and prognosis of EBVaGC according to the histological type GCLS and CGA. Methodswe retrospectively evaluated a series of EBVaGC who underwent gastrectomy with D2-lymphadenectomy. Biomarkers and tumor-infiltrating cells were evaluated by immunohistochemistry. PD-L1 was evaluated using a combined positive score (CPS). ResultsFrom a total of 30 EBVaGC, 14 (46.7%) were identified as GCLS and 16 (53.3%) as CGA (9 Intestinal, 6 diffuse, 1 undetermined). There were no significant differences in age, sex, and pTNM between GCLS and CGA. CPS-positivity and high-CD8+ was significantly higher in GCLS compared with CGA (P = 0.007 and P = 0.005, respectively). Diffuse EBVaGC had worse survival than intestinal type (P = 0.020). There was no difference in survival between GCLS and intestinal CGA (P = 0.260). In multivariate analysis, CPS and pN status were related with survival in EBVaGC. ConclusionsCGLS was associated with a predominance of CD8+ cell infiltration and PD-L1 expression. CPS and lymph node metastasis were independent factors associated with prognosis in EBVaGC. These results suggest that specifically EBV-positive GCLS may be prime candidates for PD-1 directed therapy.

Comparison between Conventional Gastric Adenocarcinoma and EBV Associated Gastric Carcinoma

Epstein Barr Virus (EBV or Human herpesvirus 4) belongs to the genus Lymphocryptoviridae, the gamma 1 subtype of the Subfamily Gamma herpes viridae and is one of the most common viruses in humans. It is present in all populations, infecting more than 95% of all individuals within the first four decades of life. In developing countries, infections occur very early in life with no specific characteristics other than the general symptoms of acute viremia. In developed countries however, the infection is usually delayed until adolescence or early childhood years where it causes infectious mononucleosis, a benign self-limiting lymphoproliferative disorder. Though the infection with EBV is benign in the acute stages and latent in the chronic phase in the vast majority of people, the virus has been demonstrated to be involved in the development of many malignancies with the list of such malignancies progressively increasing. The first association was with the endemic Burkitt’s lymphoma. Subsequently, other lymphomas (subtypes of Hodgkin’s and non-hodgkin’s lymphomas) are also known to be associated with EBV infection. Epithelial malignancies such as lymphoepitheliomas of nasopharynx and stomach are included in the list of EBV associated tumors. Tumors arise as a result of genetic and epigenetic alterations produced by the virus, which transforms the normal cell into an immortalized proliferating cell. Since Burke et al first detected EBV in undifferentiated lymphoepithelioma like gastric cancer in 1990, many researches are undertaken to prove the same. EBV expresses latent membrane protein which can be detected immune histochemically. Our study is aimed at detecting the EBV expression in gastric carcinoma cells.

Aberrant β-catenin Activity in Hepatoid Adenocarcinoma of the Stomach.

Hepatoid adenocarcinoma of the stomach (HAS) has been recognized as a rare primary gastric tumor characterized by hepatocellular carcinomalike histology. HAS often causes diagnostic confusion with conventional gastric adenocarcinoma (CGA) due to the difficulty to detect hepatoid differentiation solely based on findings from hematoxylin and eosin (H&E) staining. β-catenin is highly expressed in hepatocellular carcinoma (HCC), which is involved in the maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. Due to the scarcity of confirmed cases of HAS, there are few studies on β-catenin. 14 patients diagnosed in our hospital were selected. The clinical characteristics of 14 patients were statistically studied, and pathological specimens were analyzed by immunohistochemistry. We detected statistically significant difference in the expression of β-catenin (P = 0.000), glypican3 (P = 0.019), and hepar-1 (P = 0.007) between HAS cancer tissues and normal tissues. Furthermore, a significant correlation was found between the expression of β-catenin in HAS cancer tissue and normal tissue (Pearson correlation coefficient: 0.686, P = 0.007). Meanwhile, a significant correlation was observed between the expression of β-catenin and survival time (Spearman correlation coefficient= - 0.482, P = 0.003). However, we found the expression of β-catenin did not correlate with the tumor differentiation and size, age, gender, serum AFP levels, microinvasion, and metastasis (P > 0.05). Our findings establish β-catenin as a useful marker that can distinguish HAS from CGA and may improve the early diagnosis to guide the appropriate and timely treatment of HAS patients.

DNMT3A overexpression is associated with aggressive behavior and enteroblastic differentiation of gastric adenocarcinoma

Gastric adenocarcinoma (GA) with enteroblastic differentiation is a subset of gastric cancer with poor prognosis. RNA-Seq data of The Cancer Genome Atlas of GA (TCGA-STAD) revealed a positive correlation between SALL4, a representative enteroblastic marker, and DNMT3A expression. Here, we conducted immunohistochemical analysis of GA to clarify the clinicopathological significance of DNMT3A expression and its correlation with enteroblastic differentiation. Of the 346 cases of solitary GA analyzed, 120 (34.7%) showed unequivocal DNMT3A nuclear expression. DNMT3A expression was associated with Lauren's intestinal type, papillary and tubular architectures, high frequency of lymphatic and vascular invasion, and lymph node metastasis (each, P < 0.01). Log-rank test revealed that DNMT3A-positive cases recurred more frequently with a predilection for liver metastasis (P < 0.01) and showed poorer overall and recurrence-free survival (each, P < 0.05). With respect to surrogate markers of molecular subtypes, DNMT3A-positive cases more frequently showed p53 overexpression (P < 0.001). Consistent with the results of TCGA data analysis, DNMT3A-positive cases exhibited enteroblastic morphology (18.3% vs. 0.9%, P < 0.001) and expressed enteroblastic markers, SALL4 (32.5% vs. 3.1%, P < 0.001) and glypican-3 (22.5% vs. 4.4%, P < 0.001) more frequently than did DNMT3A-negative cases. Additionally, GAs showing enteroblastic differentiation, morphologically or immunohistochemically, expressed DNMT3A with significantly higher frequency and intensity than did conventional GAs (P < 0.001). Our findings suggest DNMT3A as a potential therapeutic target for this conventional therapy-refractory cancer subtype.

Frequent loss of heterozygosity of SMAD4 locus and prognostic impacts of SMAD4 immunohistochemistry in gastric adenocarcinoma with enteroblastic differentiation

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of gastric adenocarcinoma. Clinicopathologically, GAED is known to be aggressive and is characterized by frequent vascular invasion, lymphatic invasion, and liver metastasis even in early stages. SMAD4 was identified as a frequently deleted gene in GAED by copy number variation analysis in our previous next-generation sequencing study; therefore, we examined the clinicopathological impacts of SMAD4 in 51 cases of GAEDs (early: 17, advanced: 34). We performed Sanger sequencing for SMAD4 mutations and loss of heterozygosity (LOH) analysis of the SMAD4 locus, in addition to immunohistochemistry for SMAD4, to determine its clinicopathological correlations and impacts on survival. The frequency of LOH at the SMAD4 locus was 45.1%, and it was significantly higher in GAED compared to in conventional gastric adenocarcinoma. SMAD4 mutations were not found in any case. Reduced SMAD4 expression was found in 60.8% of cases; it was significantly correlated with advanced stages and lymph node metastasis and showed trends of larger tumor size and lymphatic invasion. Reduced SMAD4 expression in metastatic lymph nodes was found in 21 of 36 cases. Survival analysis revealed that reduced SMAD4 expression significantly affected the patient's overall survival (OS) and recurrence-free survival (RFS), although multivariate analysis showed that only liver metastasis and lymphatic infiltration (Ly+) were independent prognostic factors for OS and RFS. The SMAD4 locus is one of the susceptibility genes in this tumor, although SMAD4 mutation was not detected. Furthermore, the inactivation of SMAD4 appeared to contribute to the aggressiveness of GAED.

Comparison between Conventional Gastric Adenocarcinoma and EBV Assocated Gastric Carcinoma

Comparison between Conventional Gastric Adenocarcinoma and EBV Assocated Gastric Carcinoma

Next-generation sequencing analysis for gastric adenocarcinoma with enteroblastic differentiation: emphasis on the relationship with hepatoid adenocarcinoma

Histologically tubulopapillary structures with glycogen-rich clear cytoplasm in gastric adenocarcinoma with enteroblastic differentiation (GAED) are well known, but a solid growth pattern can also be observed as a minor component. In contrast, hepatoid adenocarcinoma (HAC) of the stomach shows many overlapping features, including solid pattern and α-fetoprotein expression. In this study, we employed next-generation sequencing (NGS) to establish a molecular/clinicopathological concept of GAED and clarify whether these two tumors should be grouped together in one category. Among 2273 primary gastric cancers treated in our hospital between 2008 and 2017, we defined 51 cases as GAEDs showing tubulopapillary or solid patterns that express at least one of the following markers: α-fetoprotein, glypican-3, or spalt-like transcription factor 4. All cases previously diagnosed as HAC in our hospital had clear cytoplasm and were included as GAEDs by histological re-evaluation and immunohistochemical findings. We performed NGS for 24 histologically typical GAEDs and Sanger sequencing for the remaining cases. The most frequently mutated gene was TP53, and almost all cases with missense mutation showed p53 overexpression. An analysis of copy number variation revealed that ERBB2 amplification was the most frequent in GAED. Additionally, HER2 immunohistochemistry and fluorescence in situ hybridization confirmed that 22% of informative cases were HER2 positive. There was no correlation between molecular/clinicopathological parameters and α-fetoprotein expression or growth patterns in GAED. Our analysis showed that GAED frequently harbors TP53 mutations and ERBB2 amplification. As with conventional gastric adenocarcinoma, trastuzumab may be effective for GAED. Furthermore, HAC may be subcategorized as a solid-type GAED.

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Background/Aims: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. Methods: We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). Results: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. Conclusion: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.

Clinicopathologic and immunohistochemical characteristics of gastric adenocarcinoma with enteroblastic differentiation: a study of 29 cases.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) has been recognized as a variant of alpha-fetoprotein (AFP)-producing gastric carcinoma, although its clinicopathologic and immunohistochemical features have not been fully elucidated. To elucidate the clinicopathologic and immunohistochemical features of GAED, we analyzed 29 cases of GAED, including ten early and 19 advanced lesions, and compared these cases with 100 cases of conventional gastric adenocarcinoma (CGA). Immunohistochemistry for AFP, glypican 3, SALL4, and p53 was performed, and the phenotypic expression of the tumors was evaluated by immunostaining with antibodies against MUC5AC, MUC6, MUC2, CD10, and caudal-type homeobox 2 (CDX2). Lymphatic and venous invasion was more frequent in GAED (76 and 72 %) than in CGA (41 and 31 %; P ≤ 0.001). Lymph node metastasis was more frequently observed in GAED (69 %) than in CGA (38 %; P = 0.005), as were synchronous or metachronous liver metastases (GAED, 31 %; CGA, 6 %; P ≤ 0.001). Immunohistochemically, all GAED were positive for at least one of three enteroblastic linage markers (AFP, glypican 3, and SALL4). Glypican 3 was the most sensitive marker (83 %) for GAED, followed by SALL4 (72 %) and AFP (45 %), whereas no CGA was positive. Furthermore, the rate of positive p53 staining was 59 % in GAED. Regarding the mucin phenotype, CD10 and CDX2 were diffusely or focally expressed in all GAED cases. Invasive areas with hepatoid or enteroblastic differentiation were negative for CD10 and CDX2. Clinicopathologic features of GAED differ from those of CGA. GAED shows aggressive biological behavior, and is characteristically immunoreactive to AFP, glypican 3, or SALL4.

Alteration in the Wnt/β-catenin signaling pathway in gastric neoplasias of fundic gland (chief cell predominant) type

Gastric neoplasia of chief cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar cells mimicking chief cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in addition to nuclear β-catenin immunolabeling and direct sequencing of members of the Wnt/β-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear β-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear β-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/β-catenin pathway.

Lymphoepithelioma-like gastric carcinoma: an unusual consequence of Epstein-Barr virus infection in an HIV-infected woman

Lymphoepithelioma-like-gastric carcinoma (LEL-GC) is an Epstein-Barr virus (EBV)-associated neoplasm of the stomach reported to have a better prognosis than conventional gastric adenocarcinoma. Unlike other EBV-associated malignancies, particularly lymphoproliferative disorders and undifferentiated nasopharyngeal carcinoma, for which risk has been shown to increase in human immunodeficiency virus (HIV) infection, LEL-GC remains rare; only one HIV-infected patient with LEL-GC has been reported previously. We describe an aggressive case of EBV-associated LEL-GC in a woman co-infected with HIV 1 and hepatitis C virus. In situ hybridization of an endoscopic biopsy specimen for EBV-encoded small RNA confirmed the presence of this agent exclusively in the gastric cancer cells. Our patient had recently started antiretroviral therapy, suggesting that immune reconstitution may have been a factor in presentation of this tumour.

Clinicopathological and molecular characteristics of Epstein–Barr virus‐associated gastric carcinoma: A meta‐analysis

There is conflicting data regarding the clinicopathological significance of the risk factors associated with Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC). To address this controversy, we performed a meta-analysis for the clinicopathological and molecular characteristics of EBVaGC. The relevant published studies were reviewed according to the defined selection criteria. The effect sizes of the outcome parameters were estimated by an odds ratio or a weighted mean difference. This meta-analysis included 48 studies that encompassed a total of 9738 patients. The frequency of EBVaGC was 8.8%, and EBVaGC was significantly associated with ethnicity. It was more predominant in men and in younger individuals. Interestingly, EBVaGC was more prevalent in Caucasian and Hispanic patients than in Asian ones. EBVaGC developed most often in the cardia and body, and it generally showed the diffuse histological type. EBV was highly prevalent in the patients with lymphoepithelial carcinoma. EBVaGC was closely associated with remnant cancer and a CpG island methylator-high status, but not with Helicobacter pylori infection, a TP53 expression, and p53 mutation. In addition, EBVaGC was not significantly associated with the depth of invasion, lymph node metastasis, or the clinical stage. The clinicopathological and molecular characteristics of EBVaGC are quite different from those of conventional gastric adenocarcinoma. However, further study is needed to determine the effect of EBV on the survival of EBVaGC patients.

Relation of neuroendocrine cells to transforming growth factor-alpha and epidermal growth factor receptor expression in gastric adenocarcinomas: Prognostic implications

The presence of neuroendocrine (NE) cells in gastric adenocarcinoma (GCa) is well documented, however, their significance is controversial. There is no evidence in the literature concerning the possible effect of these cells on the expression of TGF-alpha and EGFR, which are believed to confer growth advantage to tumor cells. 101 partial or total gastrectomy specimens from patients operated for conventional gastric adenocarcinoma were included in the study. In each case immunohistochemistry was performed on sequential tissue sections for chromogranin A (ChrA), TGF-alpha and EGFR. Samples were graded based on the number of ChrA-positive cells (0-3). TGF-alpha and EGFR expressions were evaluated according to both the intensity (0-2) and quantification of the positively stained areas (0-3). Follow-up data was available in 54 patients. Twenty-seven patients died of disease, while 27 patients were alive with a follow-up of at least 15 months. ChrA expression was detected in 54.4% of the tumor specimens. TGF-alpha was stained positively in 42.6% and EGFR in 49.5% of the cases. NE cells in GCa was related to TGF-alpha (p<0.0001) and EGFR expression (p<0.05), and TGF-alpha/EGFR coexpression (p<0.001). Among histopathologic variables, the presence of NE cells was significantly related to grade, stage and lymph node status. Although the presence of NE cells had no effect on survival, the expression of EGFR (p<0.0001) and TGF-alpha (p=0.002) were related to survival. The results of our study suggest that the presence of NE cells may have an effect on the expression of TGF-alpha and EGFR in GCa, and the autocrine mechanism between TGF-alpha and EGFR plays an important role in the prognosis of gastric carcinoma.

Evidence for hepatocellular differentiation in alpha-fetoprotein-negative gastric adenocarcinoma with hepatoid morphology: a study with in situ hybridisation for albumin mRNA

Hepatoid adenocarcinoma, a putative chemosensitive tumour, is defined as a tumour with aberrant hepatocellular differentiation occurring in extrahepatic organs such as the stomach, usually in the gastrointestinal tract. Differentiation in the hepatocellular direction is usually supported by the production of alpha-fetoprotein (AFP) and, more recently, albumin (ALB) mRNA. We investigated ALB mRNA to address whether adenocarcinoma with hepatoid morphology, regardless of AFP production, can be diagnosed solely by morphological criteria as a hepatoid adenocarcinoma. We performed in situ hybridisation (ISH) and immunohistochemistry (IH) for ALB mRNA on AFP-negative gastric adenocarcinomas with hepatoid morphology. AFP-positive hepatoid adenocarcinomas and AFP-negative conventional gastric adenocarcinomas were also investigated as positive and negative controls, respectively. All three gastric adenocarcinomas with hepatoid morphology with no evidence of AFP production stained positive for ALB mRNA, thus providing evidence of differentiation in the hepatocellular direction. Three of five cases of AFP-positive hepatoid adenocarcinoma of the stomach were positive for ALB mRNA, while 11 cases of AFP-negative conventional gastric adenocarcinoma were negative. The present study demonstrates that, irrespective of AFP production, gastric adenocarcinoma with morphological patterns suggestive of hepatoid differentiation should be diagnosed as hepatoid adenocarcinoma with important prognostic implications.