Invited Commentary

Abstract

Recent revisions have significantly enhanced the clinical utility of the TNM staging system for esophageal cancer. In addition to refinements in staging based on the traditional anatomical features of the tumor, this system now includes factors such as cell type, tumor grade, and tumor location in the case of squamous cell cancer. These changes have resulted in stage groupings that are more distinctive and homogenous in their prognosis. Nonetheless, there remains heterogeneity in outcomes for patients of equivalent tumor type, stage, and grade. There is great hope that the use of individual molecular markers or patterns of molecular markers will successfully subdivide existing tumor stages into subgroups that behave differently from one another. The article by Yan and colleagues [1Yan S.-M. Wu H.-N. He F. et al.High expression of Zinc-binding protein-89 predicts decreased survival in esophageal squamous cell cancer.Ann Thorac Surg. 2014; 97: 1966-1974Scopus (8) Google Scholar] investigating Zinc-binding Protein 89 (ZBP-89) expression in squamous cell cancer of the esophagus may be a step in this direction. Using an immunoreactivity score based on immunohistochemistry, the authors have shown that overexpression of ZBP-89 was associated with a significantly worse survival for tumors of all stages. The magnitude of this survival difference was dramatic, with survival in the low-expression group approximately double that in the high-expression group. It is tempting to conclude that overexpression is an indicator of more advanced disease, based on their demonstrated association with tumor stage and node positivity; however, they have also shown that it is an independent prognostic factor along with T status and node positivity. One important shortcoming of their report is that their multivariable analysis does not include several of the factors that have been recently added to the current staging system. They have classified lymph node status as a dichotomous variable, ignoring the N2/N3 subgroups. They have also not included tumor location or grade. As such, we cannot be certain whether their observed difference in survival based on ZBP-89 expression was truly independent of other accepted prognostic factors. Another important shortcoming of the study is the lack of a confirmatory study group. They have used the entire cohort of patients to determine their cutoff value for ZBP-89 expression using ROC analysis, which is certainly a well-accepted, statistically unbiased approach. However, applying this threshold to the same study group in their multivariable analysis virtually guarantees that overexpression will be a significant predictor of outcome. For these reasons, a confirmatory study is required before accepting their conclusions. If confirmed in future studies, the authors' findings studies may have important ramifications for patient management. The fact that high ZBP-89 expression is associated with decreased survival even in patients with early-stage and node-negative disease is particularly intriguing. While it is widely accepted that patients with locoregionally advanced disease should be treated with neoadjuvant therapy, the management of patients with more limited disease on preoperative staging remains a challenge. Their results suggest that overexpression of ZBP-89 may help us to identify a subgroup of patients with early-stage cancers who are at high risk of recurrence, allowing us to target postoperative adjuvant therapy to patients who are most likely to achieve a benefit. High Expression of Zinc-Binding Protein-89 Predicts Decreased Survival in Esophageal Squamous Cell CancerThe Annals of Thoracic SurgeryVol. 97Issue 6PreviewZinc-binding protein-89 (ZBP-89), a Krüppel-type four-zinc finger transcription factor, is associated with many cellular functions, including cell growth, differentiation, and apoptosis. It has been reported to be involved in several human cancers. However, ZBP-89 expression pattern and its clinical significance have not yet been investigated in esophageal squamous cell cancer. Full-Text PDF