- Diffuse or Diffuse-type gastric adenocarcinoma (DGA) is a distinct and aggressive form of gastric cancer that is characterized by its non-cohesive growth pattern, unique molecular alterations, and challenging clinical behavior.
- Unlike intestinal-type adenocarcinoma, DGA lacks glandular differentiation and is predominantly composed of poorly differentiated tumor cells or signet ring cells, which contain mucin-filled cytoplasm displacing the nucleus to the cell’s periphery.
- This subtype was first described by Lauren in 1965 and is associated with poor prognosis due to its diffuse infiltration, submucosal spread, and early metastasis.
- Histologically, DGA involves isolated cells or small clusters that infiltrate extensively into the gastric wall. These cells often remain inconspicuous due to their association with desmoplasia and chronic inflammation. Advanced stages can lead to linitis plastica, where the stomach wall becomes thickened and rigid. The diffuse growth pattern distinguishes DGA from intestinal-type adenocarcinoma, which typically forms well-defined glandular structures.
- Molecularly, DGA is categorized within the genomically stable (GS) subgroup as identified by The Cancer Genome Atlas (TCGA). Key genetic alterations include CDH1 mutations, which disrupt E-cadherin function and impair cell adhesion, facilitating tumor cell dissemination. Germline CDH1 mutations are implicated in hereditary diffuse gastric cancer (HDGC). Other notable mutations involve RHOA, which influences cytoskeletal dynamics and cell migration, as well as CTNN1A and CMTM2. Unlike the microsatellite instability (MSI) and chromosomal instability (CIN) subgroups, GS exhibits fewer somatic mutations but significant epigenetic changes, posing challenges for targeted therapy development.
- Clinically, DGA affects younger patients and shows a higher prevalence among females compared to intestinal-type adenocarcinoma. Symptoms are often vague, including dyspepsia, early satiety, weight loss, and epigastric pain. Endoscopic evaluation may reveal flat or depressed lesions with indistinct borders and pale discoloration, making accurate diagnosis difficult. Diagnostic tools such as endoscopic ultrasound (EUS), biopsy, and immunohistochemistry (e.g., E-cadherin loss and CK7 expression) are critical in confirming the condition.
- Treatment strategies for DGA are complex due to its aggressive behavior and resistance to conventional approaches. Surgical resection with total gastrectomy and D2 lymphadenectomy is the mainstay for localized disease. Systemic chemotherapy, such as the FLOT regimen, is employed in advanced cases, though response rates vary. Unlike intestinal-type adenocarcinoma, DGA rarely overexpresses HER2, limiting the efficacy of HER2-targeted therapies. Promising avenues for treatment include claudin-18.2 and FGFR inhibitors, as well as immune checkpoint inhibitors targeting PD-1/PD-L1 pathways.
- Diffuse gastric adenocarcinoma remains a challenging form of gastric cancer. Its aggressive clinical features, distinct molecular profile, and limited treatment options underscore the need for continued research into early detection methods and novel therapeutic approaches to improve outcomes for affected patients.
