Validation of tumour-negative lymph node size as a novel independent prognostic biomarker in oesophagogastric adenocarcinoma: post hoc analysis of the UK MRC OE05 and ST03 randomised trials.

BACKGROUND: The size of tumour-negative regional lymph nodes (LNnegs) may be associated with the host antitumour immune response in patients with oesophagogastric adenocarcinoma (OGAC). In the OE02 trial, larger LNnegs were independently associated with improved overall survival (OS); however, the prognostic relevance of LNneg size has not been validated in an independent OGAC population. PATIENTS AND METHODS: Resection specimens from 1367 patients from two phase III trials (OE05, n = 652; ST03, n = 715) were analysed. The largest LNneg per patient was identified on digitised slides stained with haematoxylin-eosin using an automated segmentation pipeline. Lymph node ratio [LNratio; number of metastatic lymph nodes (LNs) divided by the total number of resected LNs] was calculated for patients with stage ypN1+ cancer. Anthracotic pigment burden was quantified using a deep learning model. Associations among LNneg size, primary tumour location, recurrence, and survival were evaluated. RESULTS: LNneg size and pigment burden differed by primary tumour location. LNnegs from oesophageal/junctional cancers were larger and had greater pigment burden than those from gastric cancers (all P < 0.0001). Larger LNnegs were associated with a lower recurrence rate (P = 0.033) and lower LNratio (P < 0.0001). Patients with LNnegs with a long axis diameter >10 mm had improved OS [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.93, P = 0.0147) and progression-free survival (HR 0.80, 95% CI 0.70-0.92, P = 0.0092). Presence of large LNnegs was independently prognostic after multivariable adjustment. CONCLUSIONS: This study validates LNneg size as a novel independent prognostic biomarker in patients with locally advanced OGAC treated with cytotoxic chemotherapy and surgery. Variation in LNneg size and pigment burden by primary tumour location may suggest anatomical or microenvironmental differences in LNneg biology that may affect LN assessment and immune-related characteristics. Further studies integrating quantitative microarchitectural and immune profiling of LNnegs are warranted to clarify the mechanisms driving LNneg enlargement and the potential functional relevance of pigment deposition.