In a UK study reported in The Lancet Oncology, Lee et al found that systematic random biopsies were more likely than endoscopically targeted biopsies to first detect signet ring cell carcinoma during endoscopic surveillance of individuals meeting testing criteria for hereditary diffuse gastric cancer.

As stated by the investigators, “Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma. Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic signet ring cell carcinoma foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterization of signet ring cell carcinoma foci in hereditary diffuse gastric cancer.”

Study Details

The prospective longitudinal cohort study included 145 individuals aged ≥ 18 years at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 2005 and July 2021. A total of 92 individuals (63%) had CDH1 pathogenic variants.

The primary outcome was detection of intramucosal signet ring cell carcinoma foci. Detection rates and anatomic locations of signet ring cell carcinoma in random biopsy samples taken according to a systematic protocol were compared with those of biopsies targeted to endoscopic findings. Endoscopic lesions were evaluated with white-light and narrow-band imaging with magnification to determine the likelihood of cancerous foci.

Key Findings

Over a median follow-up of 51 months (interquartile range = 18–80 months), 58 (40%) of 145 individuals were diagnosed with invasive signet ring cell carcinoma. The first diagnosis was made with random biopsies in 29 (50%) of the 58 patients compared with targeted biopsies in 15 patients (26%); 6 patients (10%) had positive findings on both random and targeted biopsies at diagnosis. Overall, omission of random biopsies in the cohort would have led to an underdiagnosis rate of 42%.

Signet ring cell carcinoma was diagnosed in 49 (53%) of 92 individuals with CDH1 pathogenic variants and in 6 (15%) of 41 with no CDH1 pathogenic variants. Presence of CDH1 pathogenic variants was the only clinical factor associated with risk of signet ring cell carcinoma (P < .0001).

The anatomic distribution of signet ring cell carcinoma foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens (n = 76) than did targeted biopsies. For example, 40 (59%) of 68 positive targeted biopsies were derived from the antrum, whereas signet ring cell carcinoma foci in the antrum represented only a small proportion of foci identified in prophylactic total gastrectomy specimens and with random biopsy. Proportions of foci found in the antrum, cardia, fundus, and transitional zone were similar with random biopsies vs gastrectomy specimens.   

The investigators noted that previous data indicated that a pale area is the endoscopic abnormality most strongly associated with signet ring cell carcinoma foci, and they observed during the study that several characteristics of these areas were correlated with histologic findings of foci. These included round shape (vs linear morphology of scars from previous biopsy), well-demarcated borders (vs faded margins), and reproducibility of the lesion over dynamic visualization with a different angle of incident light and distance from the mucosa. On magnification, characteristics included irregular microvascular and microsurface patterns. These criteria predicted signet ring cell carcinoma with a sensitivity of 67.3% and specificity of 90.2%.

The investigators concluded, “Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer.”

Massimiliano di Pietro, MD, of the Early Cancer Institute, University of Cambridge, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the UK Medical Research Council. For full disclosures of the study authors, visit thelancet.com.