Diffuse Gastric Carcinoma Research Articles

Points to consider regarding prophylactic total gastrectomy in germline CDH1 variant carriers.

Pathogenic germline CDH1 mutation confers high risk for developing diffuse gastric and lobular breast cancers in asymptomatic carriers. In these individuals, the estimated gastric cancer risk at 80 years of age is up to 70% for males and 56% for females. Due to this high-risk predisposition, prophylactic total gastrectomy is considered a unique life-saving approach in germline CDH1 carriers, as endoscopy often fails to detect early stage diffuse gastric carcinoma. However, surgical indication is controversial in some clinical contexts, with possible contraindications. This review discusses points against and in favor of a more aggressive surgical approach for consideration during the decision-making process.

Multimodal Therapy Versus Primary Surgery for Gastric and Gastroesophageal Junction Diffuse Type Carcinoma, with a Focus on Signet Ring Cell Carcinoma: A Nationwide Study.

Diffuse type adenocarcinoma and, more specifically, signet ring cell carcinoma (SRCC) of the stomach and gastroesophageal junction (GEJ) have a poor prognosis and the value of neoadjuvant chemo(radio)therapy (nCRT) is unclear. All patients who underwent surgery for diffuse type gastric and GEJ carcinoma between 2004 and 2015 were retrospectively included from the Netherlands Cancer Registry. The primary outcome was overall survival after surgery. Kaplan-Meier curves were plotted. Furthermore, multivariable Poisson and Cox regressions were performed, correcting for confounders. To comply with the Cox regression proportional hazard assumption, gastric cancer survival was split into two groups, i.e. <90 days and >90 days, postoperatively by adding an interaction variable. Analyses included 2046 patients with diffuse type cancer: 1728 gastric cancers (50% SRCC) and 318 GEJ cancers (39% SRCC). In the gastric cancer group, 49% received neoadjuvant chemotherapy (nCT) and 51% received primary surgery (PS). All-cause mortality within 90 days postoperatively was lower after nCT (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.20-0.44; p<0.001). Also after 90 days, mortality was lower in the nCT group (HR for the interaction variable 2.84, 95% CI 1.87-4.30, p<0.001; total HR 0.29*2.84=0.84). In the GEJ group, 38% received nCT, 22% received nCRT, and 39% received PS. All-cause mortality was lower after nCT (HR 0.63, 95% CI 0.43-0.93; p=0.020) compared with PS. The nCRT group was removed from the Cox regression analysis since the Kaplan-Meier curves of nCRT and PS intersected. The results for gastric and GEJ carcinomas were similar between the SRCC and non-SRCC subgroups. For gastric and GEJ diffuse type cancer, including SRCC, nCT was associated with increased survival.

Gastric Carcinoma with low ROR alpha, low E- Cadherin and High LAPTM4B Immunohistochemical Profile; is associated with unfavorable prognosis in Egyptian patients

ABSTRACT In view of multiplicity of carcinogenic pathways of gastric carcinoma (GC), poor survival and chemotherapy resistance, more analysis of these pathways is required for prediction of prognosis and developing new therapeutic targets. Knocking down of RORα; induces tumor cell proliferation and epithelial–mesenchymal transition (EMT). LAPTM4B has been suggested to be associated with EMT which promote tumor invasion. This work aimed to investigate prognostic role of RORα, LAPTM4B, and E-Cadherin expression in GC. This retrospective immunohistochemical study assesses the expression of RORα, LAPTM4B, and E-Cadherin in 73 primary gastric carcinomas. Low RORα and high LAPTM4B expression in GC cases were associated with unfavorable prognostic factors such as positive lymph nodes, and high tumor budding. E-Cadherin heterogeneous staining was associated with poor prognostic criteria, such as diffuse type GC and high tumor budding. Low RORα, high LAPTM4B, and heterogeneous E-Cadherin were the most common immunohistochemical profile in GC cases. Low RORα expression showed poor prognostic impact on overall patient survival. In conclusion, RORα and LAPTM4B may have crucial role in GC aggressiveness. The predominance of low RORα, high LAPTM4B, and heterogeneous or negative E-Cadherin immunohistochemical profile in GC cases with unfavorable pathological parameters suggested that this profile may predict tumor behavior.

ASSOCIATION OF HER2/NEU EXPRESSION WITH PATIENT PROGNOSIS IN PRIMARY GASTRIC ADENOCARCINOMA

Introduction: Gastric carcinoma is the second leading cause of cancer related deaths in the world. Aim of the present study was to determine the association of HER2 overexpression with prognostic factors in gastric adenocarcinoma affected Pakistani patients.&#x0D; Methods: For this purpose, immunohistochemical staining of gastric cancer patients (n=200) was performed. HER2 was found to be overexpressed in 70% of cases included in the study. Association of HER2 expression with age greater than 40 years at the time of diagnosis, histological types and moderately differentiated grades of primary gastric adenocarcinoma was observed.&#x0D; Results: HER2 was found to be overexpressed in 20% of cases. No association of HER2 was identified with the gender of the patients. Interestingly, HER2, overexpression was present in 75% of intestinal and 37% of diffuse type gastric adenocarcinoma. Based on tumor differentiation, well-differentiated (grade I) and moderately differentiated type (grade II) adenocarcinoma showed overexpression of HER2 in 90 and 80% patients respectively. Moreover, 60% patients having poorly differentiated adenocarcinoma (grade III) also exhibited HER2 overexpression.&#x0D; Conclusion: Due to presence of HER2 overexpression in diffuse type gastric carcinoma as well, it is suggested that every case of gastric adenocarcinoma should be tested for HER2 overexpression so that they can be offered targeted molecular therapy for better survival.

Frequency of CDH1, CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer.

The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.

P-304 CDH1 and CTNNA1 negative hereditary diffuse gastric carcinoma cases: Genetic susceptibility variants and their potential impacts

P-304 CDH1 and CTNNA1 negative hereditary diffuse gastric carcinoma cases: Genetic susceptibility variants and their potential impacts

Transcriptional activity of PTX3 gene in diffuse gastric carcinoma subtype

Transcriptional activity of PTX3 gene in diffuse gastric carcinoma subtype

Epidemiological review on Gastric cancer

The mortality rate of the patients with gastric cancer is reduced dramatically from past few years. Still the gastric cancer the major concern that is in front of health care professionals and is the second leading cause of cancer death across the world. But the trend of infection and the severity of infection differ as per location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse gastric carcinoma has been increasing, particularly in the Western countries. The severities of gastric cancer infection also differ by change in geographical location, social and economic status of the respective race as well. The main risk factors for distal gastric cancer include Helicobacter pylori infection and dietary factors; whereas gastro esophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The main aim of this review is to determine the epidemiology of gastric cancer and to discuss about available strategies for its prevention.

Investigation of CDH1 germline mutations in Turkish patients with Kaposi’s sarcoma

Abstract Objectives Kaposi’s sarcoma (KS) develops from the lining cells of blood or lymphatic vessels and may appear as red, purple, brown, or black lesions. E-cadherin, CDH1, is a cell adhesion molecule located on the surface of epithelial cells. CDH1 gene expression is downregulated in several cancers and is considered a tumor suppressor gene involved in epithelial-mesenchymal transition in carcinomas. Loss of CDH1 gene expression is observed in many carcinomas, mainly diffuse gastric carcinomas and lobular breast carcinomas, as well as skin tumors. This study investigates the CDH1 germline mutations in HIV-negative (Human Immunodeficiency) Virus KS patients in the Turkish population. Methods The study examined 25 peripheral blood mononuclear cells from KS patients using the Sanger sequencing technique. Results Sixteen exons of the CDH1 gene were sequenced, and a pathogenic functional germline mutation, HET c.2245C &gt; T, p.(Arg749Trp) rs776975632, NM _004360.5, was identified in a patient with a family history of gastric and breast cancer with a high number of lesions compared to other KS patients. Discussion: KS patients with a family history of cancer could be screened for CDH1 gene and cancer-related-gen variants in the future. Conclusions KS is a rare malignancy, and genetic analysis will benefit KS patients. Further studies are needed to describe better the variations detected in a large number of KS patients in this study.

Diffuse gastric adenocarcinoma during pregnancy and genetic counseling.

We present the case of a 38-year-old woman who, in the context of a 22-week gestation, was diagnosed with diffuse gastric adenocarcinoma. The age of the patient and the way in which the cancer presented itself, make genetic counseling mandatory to rule out hereditary diffuse gastric carcinoma syndrome. This rare entity, of autosomal dominant inheritance and closely linked to mutations in the CDH1 (in most cases) and CTNNA1 genes, is associated with a greater predisposition to develop malignant neoplasms of the breast and stomach. Genetic sequencing ruled out hereditary diffuse gastric cancer syndrome. Unfortunately, 24 months after the cesarean section, our patient dies.

Aberrant expression of SFRP1, SFRP3, DVL2 and DVL3 Wnt signaling pathway components in diffuse gastric carcinoma.

Diffuse gastric carcinoma (DGC) is characterized by poorly cohesive cells, highly invasive growth patterns, poor prognosis and resistance to the majority of available systemic therapeutic strategies. It has been previously reported that the Wnt/β-catenin signaling pathway serves a prominent role in the tumorigenesis of gastric carcinoma. However, the mechanism underlying the dysregulation of this pathway in DGC has not been fully elucidated. Therefore, the present study aimed to investigate the expression profiles of Wnt antagonists, secreted frizzled-related protein 1 (SFRP1) and secreted frizzled-related protein 3 (SFRP3), and dishevelled protein family members, dishevelled segment polarity protein 2 (DVL2) and dishevelled segment polarity protein 3 (DVL3), in DGC tissues. The association between the expression levels of these factors and the clinicopathological parameters of the patients was determined. Protein and mRNA expression levels in 62 DGC tumor tissues and 62 normal gastric mucosal tissues obtained from patients with non-malignant disease were measured using immunohistochemical and reverse transcription-quantitative PCR (RT-qPCR) analysis. Significantly lower protein expression levels of SFRP1 (P<0.001) and SFRP3 (P<0.001), but significantly higher protein expression levels of DVL2 (P<0.001) and DVL3 (P<0.001) were observed in DGC tissues compared with in control tissues by immunohistochemistry. In addition, significantly lower expression levels of SFRP1 (P<0.05) and higher expression levels of DVL3 (P<0.05) were found in in DGC tissues compared with those in normal gastric mucosal tissues using RT-qPCR. According to correlation analysis between the SFRP1, SFRP3, DVL2 and DVL3 protein expression levels and the clinicopathological characteristics of patients with DGC, a statistically significant correlation was found between the SFRP3 volume density and T stage (r=0.304; P=0.017) and between the SFRP3 volume density and clinical stage (r=0.336; P=0.008). In conclusion, the findings of the present study suggested that the Wnt signaling pathway components SFRP1, SFRP3, DVL2 and DVL3 may be aberrantly expressed in DGC tissues, implicating their possible role in the development of this malignant disease. The present data also revealed a positive relationship between SFRP3 protein expression and the clinical and T stage of DGC.

Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma: Relation to the immune cycle.

BACKGROUNDVarious histological types of gastric carcinomas (GCs) differ in terms of their pathogenesis and their preexisting background, both of which could impact the tumor immune microenvironment (TIME). However, the current understanding of the immune contexture of GC is far from complete.AIMTo clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.METHODSIn total, 50 GC cases were examined (15 cases of diffuse GC, 31 patients with intestinal-type GC and 4 cases of mucinous GC). The immunophenotype of GC was assessed and classified as immune desert (ID), immune excluded (IE) or inflamed (Inf) according to CD8+ cell count and spatial pattern. In addition, CD68+ and CD163+ macrophages and programmed death-ligand 1 (PD-L1) expression were estimated.RESULTSWe found that GCs with different histological differentiation demonstrated distinct immune contexture. Most intestinal-type GCs had inflamed TIMEs rich in both CD8+ cells and macrophages. In contrast, more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+ lymphocytes but abundant CD68+ macrophages, while mucinous GC had an IE-TIME with a prevalence of CD68+ macrophages and CD8+ lymphocytes in the peritumor stroma. PD-L1 expression prevailed mostly in intestinal-type Inf-GC, with numerous CD163+ cells observed. Therefore, GCs of different histological patterns have specific mechanisms of immune escape. While intestinal-type GC was more often related to PD-L1 expression, diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.CONCLUSIONThese data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.

MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers.

Simple SummaryEpstein–Barr virus (EBV) is associated with a variety of malignancies. In this review, we discuss EBV-encoded microRNAs and ncRNAs and consider how their detection could aid in the diagnosis, prognostication, and monitoring of treatment in patients with EBV-associated malignancies, including classical Hodgkin’s lymphoma (cHL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and gastric carcinoma (GC).EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.

Poorly cohesive gastric carcinoma. Validity of using the term; translation variants

Gastric cancer is one of the leading causes of cancer morbidity and mortality worldwide. It is common practice to use two classification systems: the Lauren classification system and the WHO classification of tumors in the morphological study of gastric carcinomas. Since 2010, the WHO classifications have included the term "poorly cohesive carcinoma", which refers to all diffuse forms of gastric cancer, including signet ring cell carcinoma and other subtypes. Despite this, the term has not been widely used in the world community, and it is almost not found in Russian literature. Only recently, after the publication of the 5th edition of the WHO classification (2019), there have been review articles where the term is used, but its name can be translated into Russian in different ways: poor-, weak -, low-adhesive, discogesive. The paper analyzes the Pubmed and Elibrary databases in order to find out the frequency of using various designations for diffuse gastric carcinoma, justifies the use of the term «poorly cohesive carcinoma», and proposes a variant of the term interpretation in Russian.

The metastatic pattern of intestinal and diffuse type gastric carcinoma – A Dutch national cohort study

IntroductionThe Lauren classification of gastric adenocarcinoma describes three histological subtypes, the intestinal, the diffuse and the mixed type carcinoma. The metastatic pattern of gastric adenocarcinoma by histological subtype has not been studied. MethodsGastric adenocarcinoma patients with metastatic disease at the time of diagnosis between 1999 and 2017 were identified through the Netherlands Cancer Registry. The Lauren classification was determined based on pathology reports archived in the Dutch Pathology Registry and was linked to individual cases in the Netherlands Cancer Registry. ResultsAmong 8 231 newly diagnosed, metastatic and evaluable gastric adenocarcinoma patients, 57 % had an intestinal type carcinoma, 38 % patients had a diffuse type carcinoma and 5 % had a mixed type carcinoma. Intestinal type carcinomas more often metastasized to the liver (57 % versus 21 %, p < 0.0001) and lungs (13 % versus 7 %, p < 0.0001), whereas diffuse type carcinomas more often metastasized to the peritoneum (58 % versus 29 %, p < 0.0001) and bones (9 % versus 6 %, p < 0.0001). Patients with a diffuse type carcinoma had a worse survival perspective regardless of the number or the location of the metastases. ConclusionIn this national cohort study, metastatic gastric adenocarcinoma of the intestinal type had a predilection for the liver and that of the diffuse type for the peritoneum.

First report of a Mexican family with mutation in the CDH1 gene

BackgroundGermline mutations in E‐cadherin (CDH1) gene are associated with autosomal‐dominantly inherited cancer syndrome characterized by diffuse gastric cancer, lobular breast cancer, and in some families, cleft lip/palate. However, there may be generations in which these neoplasms do not occur at all in a family and later on, one or another carcinoma arises, which makes it difficult for physicians to think about hereditary origin.MethodsWe report the first Mexican family with CDH1 mutation (variant c.377del).ResultsAn asymptomatic young woman underwent a search for mutations in susceptibility genes for breast cancer due to the history of this neoplasm in her mother and maternal aunt. A CDH1 mutation was detected. After an endoscopy, a diffuse gastric carcinoma was found. Later on, three generations of this family were studied. The findings are presented.ConclusionMedical communities should be aware of the contribution of this gene in the development of hereditary diffuse gastric carcinoma (HDGC) and breast cancer.

Comparison of HER-2 Amplification with Clinicopathological and Prognostic Parameters in Metastatic Gastric Carcinomas

Introduction: HER2 overexpression is present in 7 to 34% of gastric carcinomas. Several studies have demonstrated associations between HER2 overexpression and clinicopathological variables, including tumor depth, lymph node metastasis, and intestinal morphology. HER2 overexpression has been linked to shorter survival. Aim: In this study, we aimed to determine the frequency of HER2 overexpression in patients with metastatic gastric carcinoma referred to our clinic, to assess HER2 expression using immunohistochemistry (IHC) or silver in situ hybridization (SISH) and to demonstrate potential associations between HER2 expression and histopathological parameters. Materials and Methods: In this study, we assessed archival samples from 120 patients diagnosed with metastatic gastric carcinoma between 2015 and 2019 and tested for HER2 status. Samples had been obtained by endoscopic biopsy in 84 patients and gastric resection in 36 patients, whereas 36 patients were diagnosed in other health facilities and were referred to our department for consulting. Hematoxylin-eosin stained preparations were reassessed, and diagnoses were confirmed based on World Health Organization (WHO), and Lauren classifications and HER2 results were compared to previous results. HER2 status was assessed by immunohistochemistry (IHC) or silver in situ hybridization (SISH) in available paraffin-embedded tumor sections. Associations between HER2 expression levels and age, sex, tumor location, size and histological type of the tumor, lymphovascular, perineural and perinodal invasion and perinodal invasion, lymph node metastasis, and site of metastasis. Results: 84 (70%) out of 120 patients with metastatic gastric carcinoma were male, and 36 (30%) were female, and the mean age was 60.7 years (age range: 21-90 years). 84 patients had undergone an endoscopic biopsy, and 36 patients had undergone gastric resection, whereas 39 patients were diagnosed in other health facilities and were referred to our department for consulting. In total 31(25.8%) out of 120 subjects tested positive for HER2 overexpression Comparisons of histological patterns, according to Lauren's classification, indicated that intestinal type was predominant in both groups, and none of the diffuse gastric carcinomas was HER2 positive. A statistically significant intergroup difference was found with respect to the prevalence of diffuse gastric carcinoma (p=0.03). Conclusion: In our study, HER-2 gene amplification (25.8%) is compatible with the literature. Her2 positive tumors were mostly located proximally and were not observed in diffuse type. In this respect, they were found statistically significant. Keywords: Her2,SISH,Gastric Carcinoma Original Article: DOI: 10.7176/JHMN/79-07 Publication date: August 31 st 2020

A population-based study on intestinal and diffuse type adenocarcinoma of the oesophagus and stomach in the Netherlands between 1989 and 2015

AimTo investigate the nationwide time trends in incidence and survival of oesophageal and gastric adenocarcinomas according to the Laurén classification (intestinal, diffuse and mixed type). MethodsAll patients diagnosed in the Netherlands with oesophageal or gastric adenocarcinoma between 1989 and 2015 were included. A syntax was developed to determine the histological subtype based on pathology reports as archived in the Dutch pathology registry. These reports were linked to individual data from the Netherlands Cancer Registry. Relative survival was used to assess survival. ResultsThe histological subtype could be determined in 18.691 (84.1%) oesophageal and in 32.312 (83.5%) gastric adenocarcinomas. Among these, 79% were intestinal and 21% diffuse type in oesophageal cancers, compared to 55% intestinal and 44% diffuse type in gastric cancers. Relative median survival of intestinal type tumours was longer than that of diffuse type tumours, that is, 12.1 versus 9.4 months for oesophageal carcinomas, and 10.1 versus 7.6 months for gastric carcinomas, respectively. Between 1989 and 2015, the relative median survival of non-metastatic intestinal and diffuse type oesophageal adenocarcinoma improved from 12.0 to 30.0 months, and from 12.0 to 19.2 months, respectively. The same was true for intestinal type gastric carcinoma (from 22.8 to 27.6 months) but for diffuse type gastric carcinoma, the increase was less (from 16.8 to 18.0 months). ConclusionIn this nationwide study, histological subtypes of oesophageal and gastric adenocarcinomas differed in incidence and survival times. These findings may call for a differentiated treatment approach.

Characterization of a short-term culture from a canine diffuse gastric carcinoma

Characterization of a short-term culture from a canine diffuse gastric carcinoma

Carcinoma breast presenting as a metastatic Kruckenberg tumor

Kruckenberg tumor is metastatic ovarian malignancy from primary gastrointestinal tract (GIT) or breast malignancy. Diffuse gastric carcinoma (linitis plastica) used to be the most common but lately there have been an increase in breast origin. It is usually found on carcinoma breast patients when we are evaluating for any metastasis. It is rare to find patients presenting with symptoms pertaining to metastasis, but not impossible. We are presenting such a rare case, where a patient presented with Kruckenberg tumor, which later was found to be a case of carcinoma breast. The prognosis of such patients are poor.