Shrinkage versus fragmentation response in neoadjuvantly treated oesophageal adenocarcinoma: significant prognostic relevance

Abstract

Aims No consensus exists on the clinical value of tumour regression grading (TRG) systems for therapy effects of neoadjuvant chemoradiotherapy (nCRT) in oesophageal adenocarcinoma. Existing TRG systems lack standardization and reproducibility, and do not consider the morphological heterogeneity of tumour response. Therefore, we aim to identify morphological tumour regression patterns of oesophageal adenocarcinoma after nCRT and their association with survival. Methods and results Patients with oesophageal adenocarcinoma, who underwent nCRT followed by surgery and achieved a partial response to nCRT, were identified from two Dutch upper‐gastrointestinal (GI) centres (2005–18; test cohort). Resection specimens were scored for regression patterns by two independent observers according to a pre‐defined three‐step flowchart. The results were validated in an external cohort (2001–17). In total, 110 patients were included in the test cohort and 115 in the validation cohort. In the test cohort, two major regression patterns were identified: fragmentation (60%) and shrinkage (40%), with an excellent interobserver agreement (κ = 0.87). Here, patients with a fragmented pattern had a significantly higher pathological stage (stages III/IV: 52 versus 16%; P < 0.001), less downstaging (48 versus 91%; P < 0.001), a higher risk of recurrence [risk ratio (RR) = 2.9, 95% confidence interval (CI) = 1.5–5.6] and poorer 5‐year overall survival (30 versus 80% respectively, P = 0.001). Conclusions The validation cohort confirmed these findings, although had more advanced cases (case‐stages = III/IV 91 versus 73%, P = 0.005) and a higher prevalence of fragmented‐pattern cases (80 versus 60%, P = 0.002). When combining the cohorts in multivariate analysis, the pattern of response was an independent prognostic factor [hazard ratio (HR) = 1.76, 95% CI = 1.0–3.0]. In conclusion, we established an externally validated, reproducible and clinically relevant classification of tumour response.

Relevance of shrinkage versus fragmented response patterns in rectal cancer

“…This study is in line with earlier observations in oesophageal cancers, suggesting that there are universal patterns of response in gastrointestinal tract tumours 26 . In rectal cancer, we observe a similar, although less pronounced, prognostic impact.…”

“…This study is in line with earlier observations in oesophageal cancers, suggesting that there are universal patterns of response in gastrointestinal tract tumours. 26 In rectal cancer, we observe a similar, although less pronounced, prognostic impact. A reason behind this might be the relatively favourable life expectancy of rectal cancer compared to oesophageal cancer, 29,30 even in tumours with a fragmented pattern.…”

“…By application of response patterns, we can link response to the stage and the presence of residual tumour cells in deeper layers of the bowel wall. In this study, as well as in oesophageal carcinoma, 26 we have shown that implementing our definition and the three‐step flowchart classification provided a more reliable and reproducible classification of response patterns, thus solving a practical issue with response classification. Moreover, its clinical relevance is consistent with the previous literature 17,23,24,26 …”

“…; Figure 1). 26 Difficult cases were discussed among the same researchers to reach consensus and, in case of discordance, consultation with an expert gastrointestinal pathologist (I.D.N.) was carried out.…”

Rectal tumor fragmentation as a response pattern following chemoradiation

“…In this way, tumor regression is not directly correlated to ypTN downstaging. A potential explanation for this histologic discrepancy is a tumor response pattern described as fragmentation, as opposed to the more commonly considered response pattern of tumor shrinkage which occurs in the direction of the mucosa ( 21 ). Following nCRT, residual tumor can be measured according to distribution of viable tumor cells within submucosa and/or muscularis propria in relation to the proportion of fibrosis.…”