Comparative study of endoscopic surveillance in hereditary diffuse gastric cancer according to CDH1 mutation status

Abstract

Background and aims: Hereditary diffuse gastric cancer (HDGC) accounts for 1% of gastric cancer cases. For patients with a germline CDH1 mutation, risk-reducing gastrectomy is recommended. However, for those delaying surgery or for families with no causative mutation identified, regular endoscopy is advised. This study aimed to determine the yield of signet ring cell carcinoma (SRCC) foci in individuals with a CDH1 pathogenic variant compared with those without and how this varies with successive endoscopies.

Methods: Patients fulfilling HDGC criteria were recruited to a prospective longitudinal cohort study. Endoscopy was performed according to a strict protocol with visual inspection followed by focal lesion and random biopsy sampling to detect foci of SRCC. Survival analysis determined progression to finding of SRCC according to CDH1 mutation status. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and 36-item Short Form Health Survey questionnaires assessed quality of life before surveillance and each endoscopy.

Results: Eighty-five individuals fulfilling HDGC criteria underwent 201 endoscopies; 54 (63.5%) tested positive for CDH1 mutation. SRCC yield was 61.1% in CDH1 mutation carriers compared with 9.7% in noncarriers, and mutation-positive patients had a 10-fold risk of SRCC on endoscopy compared with those with no mutation detected (P < .0005). Yield of SRCC decreased substantially with subsequent endoscopies. Surveillance was associated with improved psychological health.

Conclusions: SRCC foci are prevalent in CDH1 mutation carriers and can be detected at endoscopy using a standardized, multiple biopsy sampling protocol. Decreasing yield over time suggests that the frequency of endoscopy might be reduced. For patients with no CDH1 pathogenic variant detected, the cost-to-benefit ratio needs to be assessed in view of the low yield.

Figure 1

Detection of signet ring cell carcinoma (SRCC) on endoscopy. A, Examples of endoscopic lesions associated with foci of SRCC. From left to right: pale area, polyp, mucosal erosion. B, An additional case of a pale area positive for SRCC, with corresponding autofluorescence imaging and narrow-band imaging magnification image and histology showing a focus of SRCC. Narrow-band imaging magnification demonstrates loss of pit and irregular vessels.

Figure 2

Risk of signet ring cell carcinoma (SRCC) on endoscopy by CDH1 mutation status. A, Survival analysis of progression to SRCC on endoscopy by CDH1 mutation status. B, Cumulative hazard for SRCC by CDH1 mutation status. CDH1-NPVD, CDH1 no pathogenic variant detected.

Figure 3

Timing of findings of signet ring cell carcinoma on endoscopy in CDH1+ patients.