Individual risk calculator to predict lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study

Abstract

<b>Background and study aims:</b> There is a risk for lymph node metastases (LNM) after endoscopic resection of early esophageal adenocarcinoma (EAC). The aim of this study was to develop and internally validate a prediction model that estimates the individual metastases risk in patients with pT1b EAC. <b>Patients and methods:</b> This is a nationwide, retrospective, multicenter cohort study. Patients with pT1b EAC and treated with endoscopic resection and/or surgery between 1989 and 2016 were included. Primary endpoint was the presence of LNM in surgical resection specimen or the detection of metastases during follow-up. All resection specimens were histologically reassessed by specialized gastrointestinal pathologists. Subdistribution hazard regression analysis was used to develop a prediction model. The discriminative ability of this model was assessed using the c-statistic. <b>Results:</b> 248 patients with pT1b EAC were included. Metastases were seen in 78 patients, and the 5-year cumulative incidence was 30.9% (95% CI 25.1%-36.8%). The risk for metastases increased with submucosal invasion depth (subdistribution hazard ratio [SHR] 1.08, 95% CI 1.02-1.14, for every increase of 500 μm), for tumors with lymphovascular invasion (SHR 2.95, 95% CI 1.95-4.45) and for larger tumors (SHR 1.23, 95% CI 1.10-1.37, for every increase of 10 mm). The model demonstrated a good discriminative ability (c-statistic 0.81, 95% CI 0.75-0.86). <b>Conclusions:</b> One third of patients with pT1b EAC experienced metastases within 5 years. The probability for developing post resection metastases can be estimated with a personalized predicted risk score incorporating tumor invasion depth, tumor size and lymphovascular invasion. This model needs to be externally validated before implementation into clinical practice.

Lymphovascular invasion quantification could improve risk prediction of lymph node metastases in patients with submucosal (T1b) esophageal adenocarcinoma

“…This study was approved by all Medical Ethical Review Committees in the participating centers (MEC‐2016‐050). A detailed description of in‐ and exclusion criteria, data collection, patient selection, reassessment of histopathological variables, and the statistical analyses can be found in our previous study, as the present study is an extension to our previous study 6 . Histopathological reassessment was performed by three gastrointestinal pathologists for 84 patients to calculate the inter‐observer agreement as explained in our previous study 16 .…”

“…In the prediction model of the present study, quantification of LVI on a 4‐tier assessment scale is incorporated instead of interpreting LVI as a dichotomous parameter. The same patient cohort is used, and the same statistical analyses are performed as in our previous study 6 . The added value of LVI quantification to the model was assessed using the likelihood ratio test and quantified by the increase in Harrell's concordance index ( c ‐statistic).…”

“…The presence of lymph node metastases (LNM) is an important prognostic factor in submucosal esophageal adenocarcinoma (pT1b EAC) 1 . Various risk factors for LNM have been identified including depth of infiltration, grade of differentiation, and lymphovascular invasion (LVI) 2–6 …”

“…We recently developed a prediction model based on histopathological risk factors to estimate the risk for metastases in patients with pT1b EAC 6 . We showed that LVI was the strongest predictor for metastases with an estimated 5‐year risk of developing metastases ranging between 15.7% and 70.1% for pT1b EAC with LVI as compared to 5.9%–35.2% for those without LVI 6 . Other studies reported a worse 5‐year survival in patients with pT1b EAC with LVI compared to pT1b EAC without LVI (27% vs. 77%, p < 0.01) 7,8 …”

“…LVI is often reported as a dichotomous parameter, either absent or present 6–14 . Intuitively, there may be a differential metastatic risk in case of only a single LVI focus versus a case with extensive LVI.…”