Conventional tumor grading systems based on the degree of tumor differentiation may not always be optimal because of difficulty in objective assessment and insufficient prognostic value for decision making in colorectal cancer (CRC) treatment. This study aimed to determine the importance of assessing the number of poorly differentiated clusters as the primary criterion for histologic grading of CRC. Five hundred consecutive patients with curatively resected stage II and III CRCs (2000 to 2005) were pathologically reviewed. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a ×20 objective lens in a field containing the highest number of clusters. Tumors with <5, 5 to 9, and ≥10 clusters were classified as grade (G)1, G2, and G3, respectively (n=156, 198, and 146 tumors, respectively). Five-year disease-free survival rates were 96%, 85%, and 59% for G1, G2, and G3, respectively (P<0.0001). Poorly differentiated clusters affected survival outcome independent of T and N stages and could help in more effective stratification of patients by survival outcome compared with tumor staging (Akaike information criterion, 1086.7 vs. 1117.0; Harrell concordance index, 0.73 vs. 0.67). The poorly differentiated cluster-based grading system showed a higher weighted κ coefficient for interobserver variability (5 observers) compared with conventional grading systems (mean, 0.66 vs. 0.52; range, 0.55 to 0.73 vs. 0.39 to 0.68). Our novel histologic grading system is expected to be less subjective and more informative for prognostic prediction compared with conventional tumor grading systems and TNM staging. It could be valuable in determining individualized postoperative CRC treatment.

The proposed histologic DR categorization directly reflects tumor behavior in a modulating stromal environment and could provide valuable prognostic information for CRC patients.

Although recent findings of cancer biology research indicate that prognostic power arises from genes expressed by stromal cells rather than epithelial cells, desmoplastic reaction (DR) has not been completely examined as a prognostic marker for colorectal cancer. A pathologic review of 821 stage II and III patients who underwent R0 resection for colorectal cancer at 4 independent institutions was conducted. DR was classified as mature, intermediate, or immature based on the existence of hyalinized keloid-like collagen and myxoid stroma at the extramural desmoplastic front. Totally, 325, 282, and 214 patients were classified as having mature, intermediate, and immature DR, respectively. DR significantly influenced the recurrence rate in the liver, lung, and peritoneum (P≤0.0001 to 0.01). Five-year relapse-free survival (RFS) rate was the highest in the mature group (85.7%), followed by the intermediate (77.3%) and immature (50.4%) groups. A significant adverse impact of immature stroma on RFS was observed in subset analyses of the 4 institutions. Multivariate analysis revealed that DR, along with T and N stages, is an independent prognostic factor. On the basis of Harrell's concordance index, the prognostic power of DR categorization (0.67) in stratifying RFS was greater than any other conventional prognostic factors, including TNM (0.64), N (0.62) and T stages (0.59), venous invasion (0.59), and tumor grade (0.54). Characterizing DR based on the histologic products of activated fibroblasts is valuable for evaluating prognostic outcomes. To our knowledge, this is the first study reporting a greater prognostic power of histology of the fibrotic stroma than that of tumor factors.

Favorable anticancer immunity occurred after CRT for rectal cancer by altering TIL subsets. A high CD8/FOXP3 IEL ratio before CRT and a high CD8+ STL density after CRT were associated with a favorable clinical outcome.

Cytoplasmic pseudo-fragments may be a marker for an activated budding phenotype that is associated with cell motility and increased invasiveness in CRC and is independent of the extent of budding.