A Novel Grading System Based on Tumor Budding and Cell Nest Size Is a Strong Predictor of Patient Outcome in Esophageal Squamous Cell Carcinoma

Abstract

The determination of prognosis in patients with esophageal squamous cell carcinoma (ESCC) is primarily based on staging according to the TNM-classification, whereas conventional grading is of minor clinical importance because of its deficiencies in prognostic patient stratification. Recently, a novel, highly prognostic grading scheme based on budding activity and cell nest size has been proposed for squamous cell carcinoma (SCC) of both pulmonary as well as oral origin. In order to investigate the utility and transferability of this approach to ESCC, we evaluated budding activity and cell nest size, as well as other histomorphologic characteristics, in a cohort of 135 primarily resected tumors and correlated the results with clinicopathologic and outcome parameters. High budding activity and small cell nest size showed a strong association with reduced overall, disease-specific, and disease-free survival (P<0.001, respectively) in ESCC. The combination of both markers in a 3-step grading system showed excellent prognostic separation of well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) carcinomas (P<0.001). The hazard ratio for disease-free survival in multivariate analysis under inclusion of stage was 2.97 for G2 and 5.42 for G3 ESCC (P<0.001). World Health Organization-based grading had no prognostic impact. Taken together, our data prove the value of tumor budding and cell nest size as excellent outcome predictors in ESCC and validate the utility of a previously established grading scheme proposed for oral and pulmonary SCC in this tumor entity. Ultimately, these combined efforts may result in a universal grading system for SCC regardless of the site of origin.

Introducing a novel highly prognostic grading scheme based on tumour budding and cell nest size for squamous cell carcinoma of the uterine cervix

“…While the effect of cell nest size on survival has not yet been investigated in cervical SCC, tumour budding on its own has recently been linked with a dismal prognosis in a comparatively large series of early stage cervical cancers , a finding that is in line with the conclusions of various other studies, that investigated this parameter in SCCs of other anatomic sites .…”

Does evaluation of tumour budding in diagnostic biopsies have a clinical relevance? A systematic review

“…Tumour budding is a hallmark of cancer invasion and has been recently validated as a promising prognostic marker in colon cancer, 23 oesophageal cancer, 24 pancreatic cancer, 25 lung cancer 7 and oral cancer. 26 Interestingly, the meta-analyses conducted on the published studies confirm the prognostic value of tumour budding in oesophageal, colorectal and oral cancers.…”

Impact of tumor budding in head and neck squamous cell carcinoma: A meta‐analysis

“…8 However, the high intensity of TB was not always correlated with pathological poor differentiation, 9,10 suggesting that TB cells may have a different prognostic role compared with tumor grade in cancer. Currently, accumulating evidence supports the idea that TB can provide the most useful prognostic information in many solid tumors, including colorectal cancer, 30,31 colon cancer, 32 lung cancer, 33,34 esophageal SCC, 35 pancreatic cancer, 36 breast cancer, 37 cutaneous SCC, 38,39 and OSCC. 12 In our previous studies, we demonstrated that TB was correlated with poor prognosis and LNM, which was independent of TNM classification in oral tongue SCC.…”