Confocal endomicroscopy diagnostic criteria for early signet-ring cell carcinoma in hereditary diffuse gastric cancer.
BACKGROUND: Recognition of early signet-ring cell carcinoma (SRCC) in patients with hereditary diffuse gastric cancer (HDGC) undergoing endoscopic surveillance is challenging. We hypothesized that probe-based confocal laser endomicroscopy (pCLE) might help diagnose early cancerous lesions in the context of HDGC. The aim of this study was to identify pCLE diagnostic criteria for early SRCC. METHODS: Patients with HDGC syndrome were prospectively recruited and pCLE assessment was performed on areas suspicious for early SRCC and control regions during an endoscopic surveillance procedure. Targeted biopsies were taken for gold standard histologic assessment. In Phase I two investigators assessed video sequences off-line to identify pCLE features related to SRCC. In Phase II pCLE diagnostic criteria were evaluated in an independent video set by the investigators blinded to the histologic diagnosis. Sensitivity, specificity, accuracy, and interobserver agreement were calculated. RESULTS: Forty-two video sequences from 16 HDGC patients were included in Phase I. Four pCLE patterns associated to SRCC histologic features were identified: (A) glands with attenuated margins, (B) glands with spiculated or irregular shape, (C) heterogenous granular stroma with sparse glands, (D) enlarged vessels with tortuous shape. In Phase II, 38 video sequences from 15 patients were assessed. Criteria A and B and C had the highest diagnostic accuracy, with a κ for interobserver agreement ranging from 0.153 to 0.565. A panel comprising these 3 criteria with a cut-off of at least one positive criterion had a sensitivity of 80.9% (95%CI:58.1-94.5%) and a specificity of 70.6% (95%CI:44.0-89.7%) for a diagnosis of SRCC. CONCLUSIONS: We have generated and validated off-line pCLE criteria for early SRCC. Future real-time validation of these criteria is required.
Acknowledgements: We thank the staff of the Cambridge Clinical Research Center and the research nurses Tara Evans, Bincy Alias and Michele Bianchi for their help with endoscopic procedures and sample collection. We would like to thank Dr Shalini Malhotra, Dr Ahmad Miremadi, Dr Monika Tripathi and Dr James Chan for providing expert review of pathology specimens. We also thank Dr Mark Tischkowitz for genetic counselling, Dr Hisham Ziauddeen and Professor Paul Fletcher for psychological support; Mr Richard Hardwick for clinical management and Professor Carlos Caldas for his overall intellectual contribution to Familial Gastric Cancer Study.
Funder: ESOTRAC 732720
Funder: Medical Research Council
Funder: Experimental Cancer Medicine Center
Funder: Cambridge Biomedical Research Center