CDH1 Across Disciplines: Pathology, Surveillance, and Surgery!

Mehul Trivedi, MD - Communications Committee Member

We heard from Dr. Namrata Setia from the University of Chicago and Dr. Paul Mansfield from MD Anderson Cancer Center, who shared their expertise on the pathology, surveillance, and surgical management of hereditary diffuse gastric cancer (HDGC).

We began by reviewing the genetics and clinical features of HDGC, an autosomal dominant cancer predisposition syndrome caused primarily by pathogenic variants in CDH1, and less commonly CTNNA1. Although the lifetime risk of diffuse gastric cancer varies based on family history, gastric cancer remains the leading cause of mortality in affected individuals. We reviewed the current criteria for genetic testing, highlighting the importance of recognizing both family history and key pathological findings, including in situ signet ring cells and pagetoid spread, that should prompt referral for genetic counseling.

Dr. Setia then discussed the unique pathological features and progression of HDGC. Unlike intestinal-type gastric cancer, HDGC often develops beneath grossly normal-appearing gastric mucosa and consists of numerous microscopic foci of intramucosal signet ring cell carcinoma. She emphasized that identifying every focus of signet ring carcinoma is not the primary goal of surveillance. Rather, clinicians should focus on detecting deeper or more extensive lesions, as well as evolving endoscopic and histologic features that may signal progression toward clinically significant disease. She also reviewed emerging molecular markers, including fibronectin, FAK, and STAT3 activation, that may help distinguish indolent lesions from those with greater malignant potential, while highlighting the need for improved predictors of progression.

Dr. Mansfield followed with an overview of current management strategies, focusing on the challenges of balancing endoscopic surveillance with prophylactic total gastrectomy. While surveillance aims to detect occult signet ring cell carcinoma and identify mucosal abnormalities suggestive of invasive disease, its sensitivity remains imperfect and false-negative endoscopies are common. Conversely, prophylactic gastrectomy significantly reduces cancer risk but is a life-altering operation with important long-term nutritional and quality-of-life implications. He emphasized that management decisions should be individualized, taking into account family history, patient preferences, and care at experienced, high-volume centers.

The Q&A session explored the long-term consequences of prophylactic gastrectomy, including hypoglycemia and nutritional challenges, as well as the evolving pathologic terminology surrounding early signet ring cell lesions. The consensus was that further work needs to be done to better distinguish between more indolent pathologic features and those that harbor markers suggestive of progression.

Many thanks to Dr. Setia and Dr. Mansfield for sharing their expertise, and to everyone who joined the discussion. We look forward to seeing you at the next CGA-IGC webinar!

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