This study investigated the long-term outcomes and prognostic factors for stage II CC, according to the tumor sidedness. It confirmed that tumor sidedness has a major influence on prognosis. The main clinicopathological findings of this study were that stage II RCC was more frequent in more elderly patients and was characterized by a higher number of dissected lymph nodes, when compared with stage II LCC patients. Furthermore, tumor sidedness was an independent prognostic factor for OS, and the number of HLNs and gender were independent factors for both OS and DFS. For decades, there have been many suggestions that tumor location in CC potentially influences prognosis because of clinical and biological differences. Furthermore, it appears that tumors arising in right colonic lesions have different molecular and genetic pathways, when compared with those arising in left colonic lesions[3,13,19].
In related studies, it was reported that defective mismatch repair genes, high microsatellite instability (MSI-H), BRAF/KRAS mutations, and CpG island methylator phenotype positive were the notable characteristics of RCC, whereas LCC was characterized by frequent NRAS and p53 mutations[4,13,20–22]. In metastatic CRC, these molecular and genetic features of CRC by tumor location have been associated with prognosis, and the treatment, such as 5-fluorouracil-based chemotherapy or anti-EGFR therapy[19,23,24]. Meanwhile, in stage II CC, the efficacy and role of adjuvant chemotherapy is still uncertain[16,25]. In addition, there is an ongoing debate over which factors are high risk in the prognosis for stage II CC. Although tumor sidedness is not included as a stage II high-risk factor in the current guidelines, attention must be paid to tumor location in view of these molecular biological differences.
Several previous reports have indicated that RCC patients have lower survival rates than those with LCC. For example, Meguid et al. reported the survival analysis of 77,978 CRC patients, using the large population database. They found that median survival for RCC was 78 months, compared with 89 months for LCC (p < 0.001), indicating poor prognosis for RCC patients. Mejri et al. also reported the prognostic impact of tumor location for stage II/III CC. Two hundred and three patients with stage II/III CC were analyzed, and it was found that 5 year OS was significantly worse in RCC than in LCC (65% vs. 82%, HR: 2.07; 95% CI: 1.05–4.09; p = 0.03). A systemic review and meta-analysis of prognostic survival associated with tumor localization was reported in Italy. Petreli et al. analyzed 66 studies, which included 1,437,846 CRC patients. They revealed that LCC patients had a low mortality compared with RCC (HR: 0.82; 95% CI: 0.79–0.84; p < 0.01). This trend was independent of tumor staging, race, present or absent of adjuvant chemotherapy, and year of research. These findings are compatible with our results.
One notable evaluation factor based on tumor sidedness is the number of HLNs. In stage II CRC, current guidelines suggest that fewer than 12 lymph nodes harvested is considered a high-risk factor[6,7]. Low lymph node yields may result in positive lymph nodes being missed and, as a result, increase the risk of stage migration[29,30]. Tsai et al. grouped 1,167 CRC patients by number of HLNs and reported that patients with low harvests (<12) had poorer OS with stages II and III CRC (stage II: p < 0.0001; stage III: p = 0.001). In the present study, similar results were obtained, and multivariate analysis showed that the number of lymph nodes was a significantly independent factor for both OS and DFS. Furthermore, the number of HLNs was higher in the RCC group than in the LCC group (23.8 vs. 19.2, p = 0.003). Mik et al. also reported that the total number of HLNs was higher in the RCC group (11.7 vs, 8.3 ; p = 0.0001), and these results are similar to our own findings. The reason for this was due to the differences in the resected area, depending on the tumor location. The right-sided colon mesentery may anatomically contain a more complex lymphatic system and a larger area of resection, when compared with the left-sided colon[33,34]. Therefore, the reference value for the number of lymph node dissections may be better considered separately for each tumor location.
In this study, tumor sidedness was not an independent prognostic factor for DFS, although a certain trend was observed (p = 0.065). However, tumor sidedness is an independent factor for OS in stage II CC. We speculate that RCC could have a greater potential for malignancy with poor biological behavior, once it has recurred, when compared with LCC. Therefore, our results strongly indicate that RCC should be considered as a risk factor for stage II CC. In addition, it is necessary to develop multidisciplinary treatment strategies that include tumor sidedness, as well as pathological and genomic factors.
This study has some limitations. First, the small sample size, its retrospective nature, and single-institution setting may limit the generalization of results. Second, this study did not include the status of BRAF/KRAS/NRAS mutations, MSI, sporadic mismatch repair deficiency, germline mutation-prompted Lynch syndrome, or any family history. These genomic and epigenomic characteristics should be considered, in addition to the tumor location. Therefore, it is necessary to conduct randomized controlled trials with a large sample size, including genomic information, at multiple institutions across different countries, to confirm the prognostic factors in stage II CC.