A Pathological Study of Residual Cancer in the Esophageal Wall Following Neoadjuvant Chemoradiotherapy: Focus on Esophageal Squamous Cell Carcinoma Patients with False Negative Preoperative Endoscopic Biopsies

Background: Endoscopic biopsy examinations after neoadjuvant chemoradiotherapy (nCRT) are of limited value in patients with esophageal cancer due to the high rates of false negative (FN) findings. We sought to investigate the anatomical locations of residual tumors in esophageal squamous cell carcinoma (ESCC) patients with FN endoscopic biopsies with the ultimate goal of improving their clinical management. Methods: ESCC patients with residual cancers after nCRT which were not identified by preoperative endoscopic biopsy were deemed eligible. All of the surgical specimens were re-reviewed with a special focus on (1) distribution of residual cancer in each esophageal layer; (2) tumor regression grade (TRG); and (3) shortest distance between the lumen and the residual tumor. Results: Among the 49 ESCC patients with FN biopsy results, a strong ‘layer-dependent’ tumor regression was observed. There was a preferential clearing of esophageal cancer cells located in the adventitia, followed by muscle and the submucosal (SM) and mucosal (M) layers (p < 0.001). Residual malignancies located in the muscle layer or the adventitia without simultaneous involvement of the M/SM layers were rare (n = 3; 6.1 %). TRG following nCRT did not affect the rate of M/SM involvement (p = 0.55) but was inversely associated with the distance between the lumen and residual cancer (mean distance in patients with TRG of 2, 3, and 4 was 1.1, 0.82, and 0.37 mm, respectively; p = 0.041). Conclusion: Most ESCC patients who show FN endoscopic biopsies following nCRT still have detectable lesions in the M/SM layers. Aggressive biopsy protocols may potentially improve detection rates.