Diffuse gastric cancer: histologic, molecular, and genetic basis of disease

Abstract

Gastric cancer (GC) is the fifth most common malignancy with over 1,000,000 cases diagnosed annually and is the third leading cause of cancer death globally (1). The incidence is highest in Asia (with over half of all GC cases globally diagnosed in East Asia), Eastern Europe, and South America with comparatively lower rates in Africa, North America, and Europe. Approximately 95% of gastric tumors are gastric adenocarcinomas (GAC) which can be further divided into intestinal type gastric cancer (IGC), diffuse type gastric cancer (DGC), and mixed histology based on the 1965 Lauren classification (2-4). Approximately 50% of GAC are IGC, 30% are DGC, and 15-20% are mixed or indeterminate. DGC tends to occur in younger patients and in females, while IGC typically presents in older patients and in men (5-7). In the United States, the incidence of DGC also appears to be higher in the Hispanic population compared to non-Hispanic whites (8). The overall incidence of GAC has been declining since 1973 which may be due to a decrease in chronic H. Pylori infection, decreased tobacco use, and changes in diet (9). However, during the same period of time the incidence of DGC and signet-ring cell carcinoma (SRCC) had been increasing in both Asian and Western cohorts before decreasing in recent years (10-12). Reasons for this trend, as well as differences in ethnic and racial subgroups require additional research.The etiology of DGC is diverse. While intestinal metaplasia from chronic infectious etiologies (i.e., H. Pylori) is more commonly associated with IGC rather than DGC (13), Epstein-Barr virus (EBV) appears to be associated with DGC, though the strength of this association is not as clear (4,14). Tobacco use also appears to be related to the development of DGC (15,16). However, the role of other lifestyle factors such as diet and alcohol, along with the strength of these associations, merit further research (17)(18)(19). In addition to environmental etiologies, somatic and germline mutations in a number of genes can contribute to the development of DGC. These genes include CDH1, TP53, RHOA, CTNN1A, and CMTM2 (4,[20][21][22]. Approximately 1-3% of all GCs are due to hereditary diffuse gastric cancer (HDGC), with 40% of those associated with germline mutations in CDH1 (23,24). The risk of developing DGC in patients with germline

Is advanced esophageal adenocarcinoma a distinct entity from intestinal subtype gastric cancer? Data from the AGAMENON-SEOM Registry

“…PFS and OS medians for the series of 7.7 months (95% CI 7.3-8.0) and 13.9 months (12.9-14.7), respectively, are conditioned by the exclusion of Lauren diffuse-type adenocarcinomas, which are specific to gastric cancer and are associated with worse prognosis, as well as responding differently to chemotherapy. Given that diffuse adenocarcinoma is a different entity, it has not been factored into this analysis [15,19,20,24]. Likewise, the exclusion of diffuse subtype cancers determines a high percentage of HER2+ neoplasms in this series: 45%, 33.5%, and 30.1% in GEJ-AC, EAC, and GAC, respectively, versus 15-20% in most reported studies that fail to differentiate by Lauren subtype [15,25].…”

“…The (TCGA) The Cancer Genome Atlas Research Network classification system, has recognized molecular features of EAC, which closely resemble those of chromosomal instable (CIN) gastric cancer, albeit with a gradient of molecular alterations throughout the upper gastrointestinal tract with as yet unknown clinical correlation and treatment implications [14][15][16][17][18]. Furthermore, Lauren's diffuse subtype esophagogastric adenocarcinoma displays specific clinical, histopathological, molecular, and therapeutic characteristics, regardless of having been traditionally included indistinctly with intestinal-type adenocarcinoma [15,19,20].…”

Relationship of FDG PET/CT Textural Features with the Tumor Microenvironment and Recurrence Risks in Patients with Advanced Gastric Cancers

“…Most previous studies demonstrated that the maximum SUVs of gastric cancers with signet ring cell carcinoma histopathology and diffuse types of Lauren classification were significantly lower than those of papillary/tubular adenocarcinoma and intestinal type, respectively [ 28 , 29 , 30 ]. This finding is considered to result from the distinct histopathological features of signet ring cell carcinoma and diffuse-type gastric cancer, which have a relatively small number of cancer cells with scattered distributions and rich fibrous stroma [ 30 , 31 ]. Furthermore, the distinct molecular and metabolic features of signet ring cell carcinoma, such as low expression levels of glucose transporter-1 and pyruvate kinase, also contribute to low FDG uptake [ 29 ].…”

Familial Risks and Proportions Describing Population Landscape of Familial Cancer

“…Hereditary stomach cancer is associated with mutations in the CDH1 gene and it is also manifested in Lynch (hereditary nonpolyposis colorectal cancer) syndrome related to mutations in mismatch repair genes [45][46][47][48]. Next-generation sequencing studies have identified rare germline variants in several other genes, including BRCA2 and other DNA repair genes [49][50][51]. In kidney cancer, the contribution of von Hippel-Lindau syndrome is a likely explanation for the early onset risk component [52].…”