Gastric Signet Ring Cell Carcinoma Research Articles

Gastric linitis plastica due to signet-ring cell carcinoma with Krukenberg tumors diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

Gastric linitis plastica is a rare condition characterized by the stiffening and thickening of the gastric wall, presenting a "leather bottle" appearance. It is generally associated with infiltration of poorly differentiated gastric cancer cells, but similar findings can arise due to metastases from other cancers and benign inflammatory processes. Despite advances in imaging modalities, pathological evaluation is required for diagnosis. As endoscopic mucosal biopsies may not be diagnostic, endoscopic ultrasound-guided fine-needle aspiration of the thickened stomach wall presents a potential diagnostic option. We report a case which presented with bilateral ovarian tumors and was ultimately diagnosed as gastric signet-ring cell carcinoma with Krukenberg tumors by endoscopic ultrasound-guided fine-needle aspiration of the stomach wall. The preoperative diagnosis allowed the patient to avoid surgery and to start chemotherapy for gastric cancer. We also review the existing literature on endoscopic ultrasound-guided fine-needle aspiration in the context of gastric linitis plastica.

Standard of Care and Survival for Signet-ring Cell and Non-Signet-ring Cell Gastric Cancer are More Achievable at Academic Cancer Centers

Background: Western literature lacks large-scale population studies comparing the influence of academic and high-volume (HV) versus low-volume (LV) cancer centers related to the treatment of signet-ring cell gastric carcinoma (SRGC) and non-SRGC (NSRGC) oncologic outcomes.

Estrogen Receptor Beta Prevents Signet Ring Cell Gastric Carcinoma Progression in Young Patients by Inhibiting Pseudopodia Formation via the mTOR-Arpc1b/EVL Signaling Pathway.

Signet ring cell gastric carcinoma (SRCGC) is a poorly differentiated malignancy, and can be highly dangerous in the progression stage. There is a higher male to female ratio among patients with signet ring cell carcinoma as compared to patients with non-SRCGC. ERβ has been found to express in stomach adenocarcinoma, but how it affects tumor progression remains unclear. Here, we studied estrogen receptor beta (ERβ) to explore the role of sex-associated factors in SRCGC. We analyzed the clinicopathological statistics of patients with SRCGC, and conducted a series of in vitro experiments. Immunohistochemistry showed that patients with low ERβ expression were at risk of poor prognosis and higher T stage. In vitro assays indicated that ERβ might prevent SRCGC progression by inhibiting cell proliferation and invasiveness and by promoting anoikis. Western blotting and quantitative RT-PCR proved that the mTOR–Arpc1b/EVL signaling pathway might participate in the negative regulatory role of ERβ. In conclusion, our findings show that ERβ might inhibit the malignancy of signet ring cells in patients with SRCGC, indicating that ERβ might be a potential target in adjuvant treatment.

Primary hepatic squamous carcinoma concurrent with gastric signet ring cell carcinoma demonstrated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography.

Primary hepatic squamous carcinoma concurrent with gastric signet ring cell carcinoma demonstrated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography.

Clinicopathological Evaluation of Gastric Signet Ring Cell Carcinoma: Our Experience.

AimGastric cancer is one of the most common cancers worldwide. In Turkey, stomach cancer is ranked 5th among men and 8th among women in all cancers and is located in the forefront in cancer-related deaths. Signet ring cell adenocarcinoma, which is the histopathological subtype of gastric cancer, has a poor prognosis. The incidence of signet ring cell adenocarcinoma is rising. In the present study, we aimed to describe the clinicopathologic features of signet ring cell adenocarcinoma.Materials and MethodsA total of 79 patients with 30 being female (38%) and 49 male (62%) who were diagnosed with gastric signet ring cell adenocarcinoma in the Medical Oncology Department of Ankara Numune Training and Research Hospital between January 2004 and October 2015 were retrospectively evaluated.ResultsThe baseline demographic characteristics of the patients, such as tumor localization, tumor stage, preoperative serum tumor markers, and treatment type (surgery and chemotherapy regimen), and the effects of these variables on survival and mortality were evaluated. Total surgery, stage III disease, moderate to poor grade, preoperative serum CA 19-9 and CEA levels were found as independent predictors of progression risk (p < 0.05). Each 1 ng/mL increase in preoperative serum CEA level was found to increase the risk of progression by 1.20 folds. Again, each 1 U/mL in preoperative serum CA 19-9 level was found to increase the risk of progression and mortality by 1.06 folds.ConclusionThe clinicopathologic features of signet ring cell stomach cancer were described. Tumor localization and disease, CA 19-9 and CEA levels, and treatment type (surgery and chemotherapy regimen) were effective on survival and mortality. However, further studies with larger patient groups are needed on this issue.How to cite this articleAltay SB, Akkurt G, Yılmaz N, et al. Clinicopathological Evaluation of Gastric Signet Ring Cell Carcinoma: Our Experience. Euroasian J Hepato-Gastroenterol 2020;10(2):76–84.

Treatment at an Academic Cancer Center Confers Better Survival by Stage for Signet-Ring Cell and Non-signet-Ring Cell Gastric Cancer.

The literature lacks large-scale population studies comparing survival outcomes between signet-ring cell gastric carcinoma (SRGC) and non-SRGC (NSRGC) when treatment is delivered at academic versus community cancer centers. The National Cancer Database (NCDB) from 2004 to 2016 was queried to examine the association between treatment facility category and overall survival of patients who underwent gastrectomy for resectable gastric adenocarcinoma (GAC). The study investigated 22,871 patients. Upstaging of resectable GAC to pathologic stage 4 was more evident at community centers (3.5%) than at academic centers (2.8%) for the NSRGC variant (p = 0.211), whereas it was comparable between the two facility categories for the SRGC variant (5.9% vs 6%, respectively). Patients with pathologic stage 1 or 3 NSRGC who underwent gastrectomy at academic programs had better overall survival (OS) (hazard ratio [HR], 0.68; p < 0.0001) than those who underwent gastrectomy at community centers (HR, 0.79; p < 0.0065). Similarly, patients with stage 2 SRGC had better OS when treated at academic versus community centers (HR, 0.54; p = 0.0019). No statistically significant improvement in OS was observed between patients with stage 2 NSRGC (HR, 0.84; p = 0.083) and those with stage 3 SRGC (HR, 0.78; p = 0.054) who were treated at academic centers. No survival benefit was demonstrated for stage 1 SRGC when academic and community centers were compared (p = 0.56). This is the first study based on a large-scale database in the Western population that addressed the overall survival-by-stage of two distinct GAC histologic variants. Treatment at academic centers was associated with significant improvements in OS.

A Prognostic Model for Patients With Gastric Signet Ring Cell Carcinoma.

Background:The aim of our study was to develop a nomogram model to predict overall survival (OS) and cancer-specific survival (CSS) in patients with gastric signet ring cell carcinoma (GSRC).Methods:GSRC patients from 2004 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database and randomly assigned to the training and validation sets. Multivariate Cox regression analyses screened for OS and CSS independent risk factors and nomograms were constructed.Results:A total of 7,149 eligible GSRC patients were identified, including 4,766 in the training set and 2,383 in the validation set. Multivariate Cox regression analysis showed that gender, marital status, race, AJCC stage, TNM stage, surgery and chemotherapy were independent risk factors for both OS and CSS. Based on the results of the multivariate Cox regression analysis, prognostic nomograms were constructed for OS and CSS. In the training set, the C-index was 0.754 (95% CI = 0.746-0.762) for the OS nomogram and 0.762 (95% CI: 0.753-0.771) for the CSS nomogram. In the internal validation, the C-index for the OS nomogram was 0.758 (95% CI: 0.746-0.770), while the C-index for the CSS nomogram was 0.762 (95% CI: 0.749-0.775). Compared with TNM stage and SEER stage, the nomogram had better predictive ability. In addition, the calibration curves also showed good consistency between the predicted and actual 3-year and 5-year OS and CSS.Conclusion:The nomogram can effectively predict OS and CSS in patients with GSRC, which may help clinicians to personalize prognostic assessments and clinical decisions.

Proteomic Profiling of Gastric Signet Ring Cell Carcinoma Tissues Reveals Characteristic Changes of the Complement Cascade Pathway

Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared with adenocarcinomas (ACs). The lack of a systematic molecular overview of this disease has led to slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumors and adjacent tissues, including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate the cellular heterogeneity of the tissues. The proteomes of tissues were profiled by data-independent acquisition (DIA) mass spectrometry (MS). Based on the over 6000 proteins quantified, univariate analysis and pathway enrichment revealed that some proteins and pathways demonstrated differences between SRCC and ACs. Importantly, the upregulation of a majority of complement-related proteins was notable for SRCC but not for ACs. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, and the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to establish appropriate cell models for gastric SRCC through proteomic comparison of the 15 gastric cell lines and gastric tumors. The predictions of a supervised classifier suggested that none of these gastric cell lines qualified to mimic SRCC. This study discovered that the complement cascade is activated at a higher level in gastric SRCC than in ACs.

The efficiency of D1(+) lymphadenectomy in signet ring cell carcinoma: comparison of postoperative early and late outcomes between standard lymphadenectomy and D1(+) lymphadenectomy

ABSTRACT Signet ring cell carcinoma (SRCC) is a poorly cohesive subtype of gastric cancer. It is more aggressive than other types of gastric cancer. There is no special method for its treatment, but gastrectomy and lymphadenectomy is the standard approach. The aim of this study is to investigate postoperative outcomes of D1 lymphadenectomy and D1(+)lymphadenectomy in gastric SRCC. A total of 358 cases whohad a gastrectomy performed forthe diagnosis of gastric cancer between 2013 and 2019 in Ankara University Medical Faculty, Surgical Oncology Department were retrospectively investigated. In all, 128 of the cases had SRCC in the final pathology. We separated the cases into two types,D1 lymphadenectomy and D1(+) lymphadenectomy. The 5-year survival, early mortality, hospital mortality and postoperative complication rates were evaluated. There were 59 patients in the D1 group and 64 patients in the D1(+) group.Metastatic lymph node amount and therefore N stage was found to be significantly higher in the D1(+) group (p=0.00 and p=0.03, respectively). Postoperative chyle fistula was found to be significantly higher in the D1(+) group (p=0.003). There was no statistically significant difference between the groups with regard tomean survival (p=0.065);the 5-year mean survival was 21% in the D1 group and 7% in the D1(+) group.Present findings suggest that extended lymphadenectomy does not provide a benefit in cases of SRCC.

Gastric signet ring cell carcinoma

Zemni I et al. reviewed clinic and pathological characteristics and outcomes of gastric signet ring cell carcinomas (J Gastric Surg 2020; 2(3):71-78) focusing on the major prognostic factors of progression-free survival and overall survival including hypoproteinemia, tumor size, stenosis, advanced stage, and recurrence. The majority of patients were males under 60 years of age. The data were compared with those of non-signet ring cell gastric carcinomas. There was no significant difference in the 5 years overall survival between the compared groups. The increasing incidence of aggressive tumors in an advanced stage with poor outcome is emphasized and additional comments are about gastric signet ring cell tumors that affected a female and an elderly male.

Highly expressed Claudin18.2 as a potential therapeutic target in advanced gastric signet-ring cell carcinoma (SRCC).

Advanced gastric signet-ring cell carcinoma (SRCC) is a specific type of malignant gastric cancer (GC) with distinct poorer survival. Claudin18.2 (CLDN18.2) is a promising neo-biomarker for the treatment of GC. Clinical trials of CLDN18.2-targeted antibody and T cell-based immunotherapy providing promising prospects for the treatment of GC. The effect of antibody therapy depended on the expression rate of CLDN18.2 has been found in clinical trials. This study aimed to determine the prevalence and the therapeutic value of CLDN18.2 in advanced gastric SRCC. Expression of CLDN18.2 in 105 formalin-fixed, paraffin-embedded (FFPE) tumor tissues was detected by immunohistochemistry (IHC) and evaluated according to FAST criteria. Next-generation sequencing (NGS) using 416 pan-cancer genes panel was performed to characterize the genomic landscape in 61 advanced gastric SRCC patients. Fisher's exact test was used to determine gene differences in different CLDN18.2 expression levels. A total number of 105 advanced gastric SRCC samples were analyzed, of which 95.2% (100/105) were positive stained. Moderate-to-strong CLDN18.2 expression was observed in 64.8% (68/105) of all samples. In particularly, 21.0% (22/105) samples had positive staining in more than 90% tumor cells. No significance was found between CLDN18.2 expression and overall survival (OS). NGS results showed that single nucleotide variations (SNVs) could be frequently found in TP53 (26.2%), CDH1 (19.7%), MED12 (18.0%), PKHD1 (18.0%) and ARID1A (11.5%), besides, copy number variations (CNVs) were rich in NOTCH1 (18.0%) and FLT4 (9.8%) in SRCC samples. Moreover, SNVs in GRIN2A was found in 20% of the patients who had CLDN18.2 staining in <40% of tumor cells (P=0.043), indicating CLDN18.2 expression might be related to the aberration of GRIN2A in advanced gastric SRCC. The highly expressed CLDN18.2 among advanced gastric SRCC patients that we found certified the value of CLDN18.2-targeted therapy in this specific type of GC. In addition, Analyses between CLDN18.2 expression and genetic abnormalities provided novel therapeutic options for advanced gastric SRCC.

Enhanced endoscopic detection of occult gastric cancer in carriers of pathogenic CDH1 variants.

Germline inactivating variants in the CDH1 tumor suppressor gene impart an elevated lifetime risk of diffuse gastric cancer. The current endoscopic surveillance method depends upon random gastric biopsies for early cancer detection. Asymptomatic adults with pathogenic or likely pathogenic CDH1 variants referred for endoscopic gastric cancer surveillance were included in this retrospective cohort. Upper gastrointestinal endoscopy was performed according to the consensus Cambridge method, in the early period, or a systematic (Bethesda) protocol as part of an ongoing natural history study. The primary outcome measure was cancer detection. Collectively, 135 endoscopic surveillance procedures were performed in 120 patients. Twenty-six (19%, 26/135) procedures were performed using Cambridge method and 109 (81%) using the Bethesda protocol. Gastric signet ring cell carcinomas were detected in 15% (4/26) using the Cambridge method and 36% (40/109) using the Bethesda protocol (p < 0.05). Almost half (44.2%, 53/120) of patients later elected for prophylactic total gastrectomy, of whom 51 (96%, 51/53) had a signet ring cell carcinoma (T1a) discovered by histopathology. On a per endoscopy basis, the false-negative rates of detection using Cambridge method and Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively (p < 0.01). Gastric cancer detection was more frequent with implementation of a systematic surveillance protocol in CDH1 variant carriers. Given the decision for prophylactic surgery is often made by patients in the context of family history and pathologic result of surveillance biopsies, we propose the Bethesda protocol offers patients an opportunity to make more informed decisions.

Clinical Outcomes of Mucinous Gastric Carcinomas Compared with Non-mucinous and Signet Ring Cell Carcinomas.

This study examined the clinical features and prognosis of patients with mucinous gastric carcinoma (MGC), non-mucinous gastric carcinoma (NMGC), and signet ring cell gastric carcinoma (SRC). A retrospective cohort study was performed, enrolling 65 patients with MGC from January 2007 to December 2016. During the same period, 1,814 patients with histologically proven gastric cancers underwent curative or palliative operations. One hundred and ninety-five NMGC patients were selected as the 1:3 age- and sex-matched control groups. In addition, 200 SRC patients were identified. This study evaluated the demographic features of the patients, pathologic features of the tumor, and the predictive factors, such as the recurrence-free survival and overall survival. The recurrence rates were significantly high in MGC than in NMGC or SRC (both p<0.01). The proportion of early gastric cancer was lower in the MGC group than in the other groups (p<0.01). In addition, metastatic lymph nodes were found more frequently in the MGC group (p<0.01), and the proportion of initial pT4, M1 stage, was highest in the MGC group. The recurrence-free survival and overall survival in the MGC group were significantly lower than those in the NMGC or SRC. Subgroup analysis showed that patients with the same American Joint Committee on Cancer (AJCC) stage of each cancer group showed a similar prognosis. MGC frequently presents an advanced stage with an unfavorable prognosis compared to NMGC or SRC. On the other hand, MGC of the same AJCC stage had a similar prognosis to NMGC and SRC.

Comparison of metastasis between early-onset and late-onset gastric signet ring cell carcinoma

BackgroundThere is little knowledge to date about the distant metastasis of early-onset gastric signet ring cell carcinoma (SRCC) or the difference in metastasis based on age. Therefore, we conducted a comprehensive retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database and data from our hospital.MethodsPatients were collected from the SEER database and our hospital. Univariate and multivariate logistic regression analyses and propensity score matching (PSM) were used to identify risk factors for metastasis. K-M survival curves were generated to analyse patient survival.ResultsIn total, we retrieved 2052 EOGC patients diagnosed with SRCC from the SEER database and included 403 patients from our hospital. K-M survival curves showed that late-onset SRCC patients had worse survival than early-onset patients but that late-onset SRCC patients were less likely to have distant metastasis, as validated by SEER data (OR = 0.462, 95%CI, 0.272–0.787; P = 0.004) and our data (OR = 0.301, 95%CI, 0.135–0.672; P = 0.003). Multivariate logistic regression and PSM analysis revealed that age of 45 or younger was an independent risk factor for distant metastasis.ConclusionOur study showed that distant metastasis was more common in early-onset SRCC than in late-onset SRCC. However, further studies are needed to explore the potential aetiologic basis for this disparity.

Therapeutic plasma exchange in gastric signet ring cell carcinoma presenting as microangiopathic hemolytic anemia: a rare case report

Therapeutic plasma exchange in gastric signet ring cell carcinoma presenting as microangiopathic hemolytic anemia: a rare case report

S2967 An Unusual Presentation of Metastatic Pulmonary Lymphangitic Carcinomatosis as the Primary Manifestation of Signet-Ring Cell Gastric Carcinoma

S2967 An Unusual Presentation of Metastatic Pulmonary Lymphangitic Carcinomatosis as the Primary Manifestation of Signet-Ring Cell Gastric Carcinoma

1435P Survival of T1a of gastric signet ring cell carcinoma for guidance of safe endoscopic treatment: Analysis of Collaborative Stage Data of Korean Central Cancer Registry

Early-stage gastric signet ring cell carcinoma (SRC) is a candidate of endoscopic treatment. However, there were few population-based data on lymph node metastasis and distant metastasis of gastric SRC. The aim of this study was to identify the risk of lymph node metastasis and distant metastasis in mucosal cancer, very early-stage, suitable for endoscopic treatment. Collaborative Stage Data Survey was performed by the Korean Center of Cancer Registry to establish Collaborative Stage Data (CSD) of stomach, colon, rectum, rectosigmoid junction, and breast between 2010 and 2015. In our study, from CSD, patients with gastric SRC were extracted for analysis. Variables included age, sex, diagnosis date, primary site, tumor size, histology, American Joint Committee on Cancer (AJCC) staging system, and Surveillance, Epidemiology, and End Results (SEER) summary stage. These variables were analyzed. Between 2010 and 2015, 1,335 (65.7%) patients had T1a of gastric SRC. Of them, 1,283 patients (96.1%) had no regional lymph node metastasis (LNM), but 52 (3.9%) had regional LNM. In T1a gastric SRC, 6 (0.4%) patients had distant metastasis. Estimated survival time were higher in negative distant metastasis than positive distant metastasis (8.90 vs 4.66, P<0.0001). T1a gastric SRC have lymph node and distant metastasis, which are associated with shorter survival time. These findings suggest that before endoscopic treatment, vigorous examination to find lymph node metastasis and distant metastasis should be necessary for safe endoscopic treatment.

Gastric Signet Ring Cell Carcinoma: Current Management and Future Challenges.

Recent advances in the epidemiology, pathology, molecular mechanisms, and combined modality therapy (CMT) fields have shown that gastric signet ring cell carcinoma (GSRC) should be considered a distinct cancerous entity. Clinical management of this cancer is challenging, with chemoradioresistance and poor outcomes in advanced stages. Pathological and molecular sets of GSRC demonstrate different features of poor cohesion and differentiation according to the WHO, Japanese Gastric Cancer Association, and Laurén classifications. These features also result in poor response to adjuvant and neoadjuvant chemoradiotherapy. Certain studies of GSRC showed the disputed effectiveness of hyperthermic intraperitoneal chemotherapy and immunotherapy. Our aim was to discuss how an improved understanding of these therapeutic benefits may provide better treatment selection for patients, and therefore improve survival. The challenges in the new understanding of GSRC in routine practice and pathology, and the current limitations of treatment will also be discussed.

Resectable gastric signet ring cell carcinoma: clinicopathological characteristics and survival outcomes

Background: Gastric signet ring cell carcinoma (SRCC) appears to have clinical features and survival rates particularly different from other histological types. The aim of this study was to investigate clinicopathological features and survival outcomes of SRCC and to compare them with non-signet ring cell carcinoma (NSRCC). Methods: We retrospectively studied 145 patients with non-metastatic gastric carcinoma who underwent gastrectomy in our institute from 2005 to 2015. Among them, 36 patients (9.4%) with SRCC were compared to 109 patients (90.6%) with NSRCC. Results: Patients with SRCC presented at a younger age (p=0.001) with more advanced stage III-IV disease (p=0.005) and advanced N stages with a higher rate of pN3 (p=0.0001), a higher number of invaded lymph nodes (p=0.002) and a higher rate of patients with a lymph node ratio exceeding 25% (63.9% vs 36.7, p=0.004). After a median follow up of 35.30 months, there was no significant difference in the 5 years overall (OS) survival between SRCC and NSRCC ((36.7% vs 45.7%, p=0.206).However, the 5 years progressive free survival (PFS) was significantly decreased in case of SRCC (38.7% vs 50.9%, p=0.038) with a higher rate of metastasis in (52.9% vs 29.5%, p=0.013) and peritoneal recurrence (35.3% vs 9.5%, p&lt;0.0001). The main prognostic factors of PFS and OS in SRCC were tumoral stenosis, hypoprotidemia, tumor size, depth of invasion (p=0.001), perineural and lymphovascular invasion, the UICC stage and complete surgical resection. Conclusion: Gastric SRCC have a particular clinicopathological behavior compared to NSRCC suggesting its more aggressive character.

Whole Genome Sequencing Reveals Virulence Potentials of Helicobacter pylori Strain KE21 Isolated from a Kenyan Patient with Gastric Signet Ring Cell Carcinoma.

Helicobacter pylori (H.pylori) infection is etiologically associated with severe diseases including gastric cancer; but its pathogenicity is deeply shaped by the exceptional genomic diversification and geographic variation of the species. The clinical relevance of strains colonizing Africa is still debated. This study aimed to explore genomic features and virulence potentials of H. pylori KE21, a typical African strain isolated from a native Kenyan patient diagnosed with a gastric cancer. A high-quality circular genome assembly of 1,648,327 bp (1590 genes) obtained as a hybrid of Illumina Miseq short reads and Oxford Nanopore MinION long reads, clustered within hpAfrica1 population. This genome revealed a virulome and a mobilome encoding more than hundred features potentiating a successful colonization, persistent infection, and enhanced disease pathogenesis. Furthermore, through an experimental infection of gastric epithelial cell lines, strain KE21 showed the ability to promote interleukin-8 production and to induce cellular alterations resulting from the injection of a functional CagA oncogene protein into the cells. This study shows that strain KE21 is potentially virulent and can trigger oncogenic pathways in gastric epithelial cells. Expended genomic and clinical explorations are required to evaluate the epidemiological importance of H. pylori infection and its putative complications in the study population.