Diffuse-type Gastric Carcinoma Research Articles

Diagnostic Pitfall of Gastric Signet-Ring Cells: How to Diagnose a Benign Signet-Ring Cell From a Malignant One.

Sometimes non-neoplastic changes of the gastric mucosa mimic diffuse-type gastric carcinoma, specifically signet-ring cell adenocarcinoma. In fact, gastric epithelial cells undergoing signet-ring cell change have a cellular morphology that is almost identical to signet-ring cell adenocarcinoma, often leading to misdiagnosis. Accurate recognition of signet-ring cell change is essential to avoid overdiagnosis and overtreatment of signet-ring cell adenocarcinoma. Research on this topic is limited and clinicians lack formal diagnostic tools when signet-ring cells are detected in biopsy specimens. The aims of this study are 3-fold. Firstly, to increase the awareness of both clinicians and pathologists of this rare but highly significant entity. Secondly, to report 4 additional examples of signet-ring cell change and analyze them alongside signet-ring cell adenocarcinoma to compare their morphological and phenotypic features and their evolution over time. Finally, to highlight the potential utility of endoscopic resection to confirm the diagnosis. Cells in signet-ring cell change strongly express E-cadherin, show a wild-type p53 expression, and have a low Ki67 index. In contrast, cells in signet-ring cell adenocarcinoma strongly express p53, have high proliferation rates, and show either no or weak E-cadherin staining. Genetic analysis may be useful in identifying patients at risk of hereditary early diffuse gastric adenocarcinoma, which can mimic signet-ring cell change.

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.

The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction

Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell’s invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure.

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.

Abstract 2473: Tissue factor-induced fibrinogenesis and cancer cell clustering contribute to polyclonal peritoneal metastasis in diffuse-type gastric carcinoma

Abstract Diffuse-type gastric carcinoma is characterized by highly invasive growth, massive fibrosis, and peritoneal metastasis. Peritoneal metastasis is the leading cause of death in diffuse-type gastric carcinoma; however, the underlying molecular mechanisms remain largely unknown. Recent studies have established a concept of polyclonal metastasis, in which metastases arise from circulating tumor cell clusters with high metastatic potential. Polyclonal metastasis is a cause of tumor heterogeneity that contributes to tumor progression and therapeutic resistance. However, the clonality of peritoneally metastasized tumors and the evidence for polyclonal metastasis in diffuse-type gastric carcinoma have been poorly elucidated. In this study, we utilized multicolor fluorescent lineage tracking to examine the clonality of peritoneal metastasis in mouse xenograft models. When peritoneal metastasis was induced by intraperitoneal or orthotopic injection of multicolored cancer cells, each peritoneally metastasized tumor exhibited multicolor fluorescence, showing that it contains multiclonal cancer cell populations. Peritoneal cytology and in situ fluorescent imaging of micrometastases revealed that multicolored cancer cell clusters formed within the peritoneal cavity and collectively attached to the peritoneum. In vitro, peritoneal lavage fluid or cleared ascitic fluid derived from cancer patients elicited cancer cell clustering, which was inhibited by anticoagulants. Immunofluorescence and immunoblotting revealed that cancer cell clusters formed in vitro and in vivo were associated with fibrin formation. Moreover, tissue factor knockout in cancer cells significantly reduced fibrin formation, cell clustering, peritoneal attachment, and peritoneal metastasis. In an in vitro adhesion assay, fibrin formation facilitated the cancer cell-mesothelial cell adhesion. Thus, these results demonstrate that cancer cells activate the coagulation cascade through tissue factor to form fibrin-mediated cell clusters and accelerate peritoneal attachment, leading to the development of polyclonal peritoneal metastasis. Our findings identify a novel mechanism of peritoneal metastasis that may be a potential therapeutic target. Citation Format: Makoto Miyazaki, Yuko Nagamura, Hideki Yamaguchi. Tissue factor-induced fibrinogenesis and cancer cell clustering contribute to polyclonal peritoneal metastasis in diffuse-type gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2473.

Abstract 5832: Integrinα5 mediates the direct heterocellular interaction between cancer cells and cancer-associated fibroblasts and promotes peritoneal metastasis of diffuse-type gastric carcinoma

Abstract Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric cancer characterized by rapid infiltrative growth and frequent peritoneal metastasis. Peritoneal metastasis is the main cause of poor prognosis and decreased quality of life for patients with DGC. Histologically, DGC tumor lesions are associated with massive fibrotic stroma caused by the extensive proliferation of cancer-associated fibroblasts (CAFs). Peritoneally metastasized tumors of DGC are also accompanied by abundant fibrotic stroma and CAFs. CAFs are known to promote the progression of DGC by enhancing the growth, invasion, and dissemination of tumor cells. Previously, we reported that the direct heterocellular interaction between cancer cells and CAFs is necessary for the invasion and peritoneal metastasis of DGC. In this study, we aimed to identify and target the molecules that mediate such direct heterocellular interaction. Monoclonal antibodies (mAbs) against intact DGC cells were generated and subjected to high-throughput screening to obtain mAbs that block the adhesion of DGC cells to CAFs. As a result, several such inhibitory mAbs were obtained. Immunoprecipitation and mass spectrometry revealed that all mAbs recognized integrin α5 complexed with integrin β1. Blocking integrin α5 in DGC cells abrogated the adhesion of DGC cells to CAFs. Similarly, blocking fibronectin, a ligand of integrin α5β1, deposited on CAFs blocked the heterocellular adhesion. Furthermore, administration of mAbs or knockout of integrin α5 in DGC cells suppressed their invasion led by CAFs in vitro and peritoneal metastasis in a mouse xenograft model. Analysis of the public database revealed that integrin α5 and fibronectin were highly expressed in DGC. In addition, integrin α5 and fibronectin expression levels were correlated with worse overall survival in DGC patients. Taken together, these results show that integrin α5 mediates the heterotypic cancer cell-CAF interaction during peritoneal metastasis of DGC and may thus be a promising therapeutic target. Citation Format: Hideki Yamaguchi, Shingo Miyamoto, Yoshiko Nagano, Makoto Miyazaki, Yuko Nagamura. Integrinα5 mediates the direct heterocellular interaction between cancer cells and cancer-associated fibroblasts and promotes peritoneal metastasis of diffuse-type gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5832.

Receptor Tyrosine Kinases Amplified in Diffuse-Type Gastric Carcinoma: Potential Targeted Therapies and Novel Downstream Effectors.

Simple SummaryDiffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric carcinoma with an extremely poor prognosis due to frequent peritoneal metastasis and high probability of recurrence. Its pathogenesis is poorly understood, and consequently, no effective molecular targeted therapy is available. The importance of oncogenic receptor tyrosine kinase (RTK) signaling has been recently demonstrated in the malignant progression of DGC. In particular, RTK gene amplification appears to accelerate peritoneal metastasis. In this review, we provide an overview of RTK gene amplification in DGC and the potential of related targeted therapies.Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high probability of recurrence. These clinical features and progression patterns of DGC substantially differ from those of other GC subtypes, suggesting the existence of specific oncogenic signals. The importance of gene amplification and the resulting aberrant activation of receptor tyrosine kinase (RTK) signaling in the malignant progression of DGC is becoming apparent. Here, we review the characteristics of RTK gene amplification in DGC and its importance in peritoneal metastasis. These insights may potentially lead to new targeted therapeutics.

Integrin α5 mediates cancer cell-fibroblast adhesion and peritoneal dissemination of diffuse-type gastric carcinoma.

Diffuse-type gastric carcinoma (DGC) has a poor prognosis due to its rapid diffusive infiltration and frequent peritoneal dissemination. DGC is associated with massive fibrosis caused by aberrant proliferation of cancer-associated fibroblasts (CAFs). Previously, we reported that direct heterocellular interaction between cancer cells and CAFs is important for the peritoneal dissemination of DGC. In this study, we aimed to identify and target the molecules that mediate such heterocellular interactions. Monoclonal antibodies (mAbs) against intact DGC cells were generated and subjected to high-throughput screening to obtain several mAbs that inhibit the adhesion of DGC cells to CAFs. Immunoprecipitation and mass spectrometry revealed that all mAbs recognized integrin α5 complexed with integrin β1. Blocking integrin α5 in DGC cells or fibronectin, a ligand of integrin α5β1, deposited on CAFs abrogated the heterocellular interaction. Administration of mAbs or knockout of integrin α5 in DGC cells suppressed their invasion led by CAFs in vitro and peritoneal dissemination in a mouse xenograft model. Altogether, these findings demonstrate that integrin α5 mediates the heterotypic cancer cell-fibroblast interaction during peritoneal dissemination of DGC and may thus be a therapeutic target.

SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling.

Simple SummaryDiffuse-type gastric carcinoma (DGC) is characterized by rapid infiltrative growth associated with massive stroma and frequent peritoneal dissemination, which leads to poor patient outcomes. In this study, we found that the oncogenic tyrosine phosphatase SHP2 is tyrosine-phosphorylated downstream of the amplified receptor tyrosine kinases (RTKs) Met and fibroblast growth factor receptor 2 (FGFR2) in DGC cell lines. SHP2 knockdown or pharmacological inhibition selectively suppressed the growth of DGC addicted to amplified Met and FGFR2. Moreover, targeting SHP2 abrogated malignant phenotypes, including peritoneal dissemination, of Met-addicted DGC and could overcome acquired resistance to Met inhibitors. Our findings suggest that SHP2 is a potential target for the treatment of DGC addicted to amplified RTK signaling.Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.

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.

PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification

Met gene amplification has been found in a subset of malignant carcinomas, including diffuse-type gastric carcinoma (DGC), which has a poor prognosis owing to rapid infiltrative invasion and frequent peritoneal dissemination. Met is considered a promising therapeutic target for DGC. However, DGC cells with Met gene amplification eventually acquire resistance to Met inhibitors. Therefore, identification of alternate targets that mediate Met signaling and confer malignant phenotypes is critical. In this study, we conducted a phosphoproteomic analysis of DGC cells possessing Met gene amplification and identified Pleckstrin Homology Domain Containing A5 (PLEKHA5) as a protein that is tyrosine-phosphorylated downstream of Met. Knockdown of PLEKHA5 selectively suppressed the growth of DGC cells with Met gene amplification by inducing apoptosis, even though they had acquired resistance to Met inhibitors. Moreover, PLEKHA5 silencing abrogated the malignant phenotypes of Met-addicted DGC cells, including peritoneal dissemination in vivo. Mechanistically, PLEKHA5 knockdown dysregulates glycolytic metabolism, leading to activation of the JNK pathway that promotes apoptosis. These results indicate that PLEKHA5 is a novel downstream effector of amplified Met and is required for the malignant progression of Met-addicted DGC.

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.

Histopathologic Analysis of Signet-ring Cell Carcinoma In Situ in Patients With Hereditary Diffuse Gastric Cancer.

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.

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.

Abstract 857: Identification and functional analysis of FGFR2 binding proteins in diffuse-type gastric carcinoma

Abstract Diffuse-type gastric carcinoma (DGC) is highly invasive subtype of gastric adenocarcinomas and frequently exhibit scattered peritoneal metastasis. Previous studies have shown that genes of receptor tyrosine kinases (RTKs) such as FGFR2 or Met are amplified in DGC cell lines with high frequency. Hence, these cells exhibit oncogene addiction to sustained activity of these RTKs for maintenance of malignant phenotype. In order to gain novel insight in the downstream signaling pathway of DGC-specific RTKs, phosphoproteomic analysis was performed. Phosphotyrosine-containing proteins associated with RTKs were purified through two sequential rounds of immunoprecipitation from lysates of RTK-amplified DGC cell lines. Here we will show the initial functional data of transferrin receptor (TFRC), one of the identified proteins by MS analysis. In the DCG cells with FGFR2 amplification, TFRC proteins were found to bind FGFR2 and were phosphorylated at Tyr20. Moreover, shRNA knockdown of TFRC as well as inhibitor of FGFR2 revealed effective impairment in cell proliferation. These results suggest that TFRC has essential roles in malignancy of FGFR2-dependent DGC. Citation Format: Takuya Shirakihara, Ryuichi Sakai. Identification and functional analysis of FGFR2 binding proteins in diffuse-type gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 857.

Evaluation of Expression of HER2/neu in Intestinal and Diffuse Type Gastric Carcinomas by Immunohistochemistry

Evaluation of Expression of HER2/neu in Intestinal and Diffuse Type Gastric Carcinomas by Immunohistochemistry

Differentiated thyroid cancer: Why does it affect predominantly women during the reproductive period and have higher incidence of mutual association with breast cancer?

Differentiated thyroid cancer (DTC) is markedly more common in women than men, and its occurrence and risk for poorer prognosis are associated with pregnancy. Further, it is known that there is a high frequency of co-occurrence of DTC and breast cancer. Although the underlying mechanisms that contribute to these phenomena are not entirely clear, 2 hypotheses are proposed here. First, human chorionic gonadotropin (hCG) produced by the placenta may be involved, since hCG has a similar function to stimulate the thyroid as thyroid-stimulating hormone (TSH), the latter of which is known to play a role in causing DTC and may promote breast cancer through the secretion of thyroid hormones (THs). Second, thyrotropin-releasing hormone (TRH), which is stimulated by suckling in the puerperal period, induces the secretion of not only TSH and thus indirectly THs, but also prolactin (PRL), which can accelerate the development of breast cancer. These hypotheses also explain the pregnancy-associated transient increase in breast cancer risk, while inhibition of estrogen by PRL may have a long-term preventive effect on breast cancer. Pregnancy-associated hyperthyroidism may also account for female preponderance of thyroid disease in general as well as tumors in organs that the thyroid hormone targets such as cardiac myxoma and diffuse-type gastric carcinoma.

Understanding the Rare Krukenberg Tumor: A Current Review

Krukenberg tumors represent a rare type of secondary ovarian tumors composed of mucinous signetring cells. In up to 70% of cases the primary site is a diffuse type gastric carcinoma, which disseminates to the ovary through a retrograde lymphatic pathway. The Krukenberg tumor is a good example of metastatic ovarian organotropism (“seed and soil” hypothesis).The symptoms are nonspecific and usually don’t develop until the tumors reach a certain size. The definitive diagnosis can only be made histologically after surgical resection, although imaging findings can indirectly aid in the distinction between benign-malignant and primary-secondary tumors. Immunohistochemistry is the most important diagnostic method in distinguishing primary from secondary ovarian neoplasms, and can usually detect the tissue of origin. The extremely dismal prognosis of Krukenberg tumors is attributed to the fact that they represent an advanced stage metastatic disease. Although the standard treatment is systemic chemotherapydepending on the primary site, there are rough indications that cytoreductive surgery might prolong survival in selected patients.

Micropapillary early gastric carcinoma with distinct clinicopathological features, high risk for lymph node metastasis, and dismal prognosis: a multicenter clinicopathological study of 29 cases identified in 1890 early gastric carcinoma radical gastrectomies

Clinicopathology and risk factors of lymph node metastasis (LNM) in micropapillary early (pT1) gastric carcinoma (MEGC) remain elusive because of the extreme rarity. In this multicenter study, we investigated 1890 consecutive radical resections of early gastric carcinoma diagnosed with the World Health Organization criteria and identified 29 (1.5%) MEGC cases with a small (≥5%) micropapillary component. MEGC showed a male predominance (male-to-female ratio, 21:8). Most (93.1%; 27/29) tumors invaded submucosa. Lymphovascular invasion was detected in 14 (48.3%) of 29 cases. LNM was found in 13 cases (44.8%; 11 identified with a routine hematoxylin-eosin stain and 2 additional cases with a positive pancytokeratin immunostain). Overall, independent risk factors for LNM in early gastric carcinoma included patient age of 62 years or less, female sex, noncardiac location, ulcerative pattern, tumor size of greater than 2 cm, submucosal invasion, Lauren diffuse type, lymphovascular invasion, and MEGC. In MEGC, advanced pathologic stages were demonstrated in 6 (20.7%) of 29 cases. The 5-year overall survival rate of MEGC patients was 58.6%. Submucosal invasion, lymphovascular invasion, and LNM were significantly more frequent in the MEGC group than in the non-MEGC groups. Advanced pathologic stages were significantly more common in MEGC than in nonmicropapillary Lauren intestinal- but not diffuse-type early gastric carcinomas. In conclusion, MEGC demonstrated a high propensity for lymphovascular invasion, LNM with advanced stages, and dismal prognosis.