The complexity of shapes; how the circularity of tumor nodules impacts prognosis in colorectal cancer.

The current stratification of tumor nodules in colorectal cancer (CRC) staging is subjective and leads to high interobserver variability. In this study, objective assessment of the shape of lymph node metastases (LNMs), extranodal extension (ENE) and tumor deposits (TDs) was correlated with outcome. A test and validation cohort were included from two different institutions. The test cohort consisted of 190 cases of stage III CRC. Slides with LNMs and TDs were annotated and processed using a segmentation algorithm to determine their shape. The complexity ratio was calculated for every shape and correlated with outcome. A cohort of 160 stage III CRC cases was used to validate findings. TDs showed significantly more complex shapes than LNMs with extranodal extension (ENE), which were more complex than LNMs without ENE (p<0.001). In the test cohort, patients with the highest sum of complexity ratios had a significantly lower DFS (p<0.01). When only the nodule with the highest complexity was considered, this effect was even stronger (p<0.001). This maximum complexity ratio per patient was identified as an independent prognostic factor in the multivariate analysis (HR 2.47, p<0.05). The trends in the validation cohort confirmed the results. More complex nodules in stage III CRC were correlated with a significantly worse DFS, even if only based on the most complex nodule. These results suggest that more complex nodules reflect more invasive tumor biology. Since most of the more complex nodules were diagnosed as TDs, we suggest providing a more prominent role for TDs in the nodal stage and include an objective complexity measure in their definition.