Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients

Abstract

Background: For stage I-II colon cancer a significant number (5-25%) of patients has recurrent disease within 5 years. There is need to identify these high-risk patients as they might benefit from additional treatment. Stroma-tissue surrounding the cancer cells plays an important role in the tumor behavior. The proportion of intra-tumor stroma was evaluated for the identification of high-risk patients. In addition, protein expression of markers involved in pathways related to stroma production and epithelial-to-mesenchymal transition (EMT) was analyzed: beta-catenin, TGF-beta-R2 and SMAD4.

Methods: In a retrospective study of 135 patients with stage I-II colon cancer, the amount of stroma was estimated on routine haematoxylin-eosin stained histological sections. Sections were also immunohistochemically stained for beta-catenin, TGF-beta-R2 and SMAD4.

Results: Of 135 analyzed patients 34 (25.2%) showed a high proportion of stroma (stroma-high) and 101 (74.8%) a low proportion (stroma-low). Significant differences in overall-survival and disease-free-survival were observed between the two groups, with stroma-high patients showing poor survival (OS p<0.001, HZ 2.73, CI 1.73-4.30; DFS p<0.001, HZ 2.43, CI 1.55-3.82). A high-risk group was identified with stroma-high and SMAD4 loss (OS p=0.008, HZ 7.98, CI 4.12-15.44, DFS p=0.005, HZ 6.57, CI 3.43-12.56); 12 of 14 (85.7%) patients died within 3 years. In a logistic-regression analysis a high proportion of stroma and SMAD4 loss were strongly related (HZ 5.42, CI 2.13-13.82, p<0.001).

Conclusions: Conventional haematoxylin-eosin stained tumor slides contain more prognostic information than previously fathomed. This can be unleashed by assessing the tumor-stroma ratio. The combination of analyzing the tumor-stroma ratio and staining for SMAD4 results in an independent parameter for confident prediction of clinical outcome.