S4035 Synchronous Hereditary Diffuse Gastric Cancer and Colorectal Signet Ring Cell Carcinoma Associated With CDH1 Mutation: A Case Report

Introduction: Diffuse gastric and lobular breast cancer syndrome (DGLBCS), previously termed hereditary diffuse gastric cancer (HDGC), is a rare autosomal dominant condition characterized by germline mutations in the CDH1 or CTNNA1 genes. While primarily linked to diffuse gastric cancer (DGC) and lobular breast cancer, associations with other malignancies, such as colorectal signet ring cell carcinoma (SRCC), remain poorly understood. Case Description/Methods: We report a 36-year-old man with a history of treated Helicobacter pylori infection who presented with progressive epigastric pain, early satiety, significant weight loss, and iron deficiency anemia. Imaging revealed findings suggestive of linitis plastica and peritoneal metastases. Endoscopic evaluation confirmed a large ulcerated circumferential gastric mass and a polypoid lesion in the sigmoid colon. Histopathology identified poorly differentiated adenocarcinomas with signet ring features in both locations. Immunohistochemistry and genetic analysis demonstrated CDH1 mutation in both tumors. There was no evidence to suggest that the colorectal tumor represented metastasis from the gastric primary, confirming a diagnosis of hereditary diffuse gastric cancer with synchronous colorectal SRCC. The patient underwent systemic therapy, including FOLFOX, nivolumab, and later ramucirumab and paclitaxel; however, the disease progressed to peritoneal carcinomatosis. Despite aggressive treatment, the patient ultimately transitioned to comfort care, where he subsequently deceased due to disease progression. Discussion: This case highlights a rare synchronous presentation of 2 primary signet ring cell carcinomas in the setting of a CDH1 mutation, expanding the phenotypic spectrum of DGLBCS. The absence of a family history emphasizes the importance of genetic testing even in sporadic presentations. Further research is warranted to better define the role of CDH1 in colorectal SRCC and to develop screening and therapeutic strategies for individuals with CDH1-associated cancer syndromes.