Introduction

Colon cancers (CC) are common types of cancer in both men and women. The World Health Organization has reported that there are 1.8 million new cases diagnosed as having colorectal cancer each year according to the GLOBOCAN 2018 database.¹ For the first time, in 1990, Bufill et al.² suggested that colon tumors might have biological and genetic differences according to their distal and proximal location. Colon is separated as right and left accepting the splenic flexure as the transition point. CCs of right and left colon develop from different carcinogenetic pathways and accordingly show different clinical, pathological and genetic features.^3,4,5

Despite the described biological variety, the differences between the right and left CCs in terms of prognosis are not clear yet. In recent studies, it has been reported that the prognosis is worse in metastatic patients if the primary tumor is in the right colon.^6,7,8,9 However, the effect of the location of the primary tumor on the prognosis in non-metastatic patients is still controversial.^{9,10,11,12,13,14}

In this study, our aim was to analyze the clinicopathological differences between right and left CCs and to investigate the effect of primary tumor location on recurrence and survival.

Materials and Methods

Study Protocol

In our study, prospectively collected data of 389 patients who underwent curative surgery with the diagnosis of CC between March 2011 and March 2018 in the General Surgery Clinic of the American Hospital were retrospectively analyzed. Fifty-nine patients who had hereditary cancers, synchronous tumors, tumors developed on the basis of inflammatory bowel disease, history of cancer, and underwent cytoreductive surgery were excluded from the study. Three hundred thirty patients operated with a diagnosis of right (n=155) or left (n=175) CC were included in the study. Written consent was obtained from all patients for surgery.

Right CC was defined cecum tumors, ascending colon tumors, hepatic flexure tumors or transverse colon tumors up to the splenic flexure, whereas left CC was defined splenic flexure tumors, descending colon tumors or sigmoid colon tumors up to rectosigmoid junction.

Preoperative staging was performed in all patients with colonoscopy, thorax and whole abdominal computed tomography and/or positron emission tomography. Patients who were eligible for surgery underwent curative surgery by the same surgeon (DB). In the right CC; right hemicolectomy, extended right hemicolectomy or subtotal colectomy was performed. In the left CC; left hemicolectomy, extended left hemicolectomy or anterior resection was performed. Patients who underwent simultaneous radical R0 liver surgery (resection, metastasectomy and/or radiofrequency ablation) and patients with omentum metastasis who underwent R0 omentum resection were also included in the study.

Demographic characteristics, surgical data, pathological data, recurrence and survival rates of the patients were examined and comparisons were made between the two groups. Pathology results were analyzed in terms of TNM stages, differentiation, histological type, tumor deposit, tumor perforation, lymphatic invasion, vascular invasion and perineural invasion, total number of harvested lymph nodes, tumor diameter and tumor volume, and the groups were compared statistically. Pathological examinations were performed by the same team experienced in gastrointestinal pathology.

Postoperative Treatment and Follow-up

Chemotherapy was applied to all stage III and IV patients. Chemotherapy was also applied to stage II patients with poor prognostic factors such as tumor at pathological T4 stage, perforation, obstruction, poor differentiation, presence of signet-ring cell component, lymphovascular or perineural invasion. Follow-up was performed every 3 months for the first 2 years after surgery, using physical examination, carcinoembryonic antigen, and imaging methods. In the next 3 years, follow-up was performed every 6 months.

Overall survival was defined as the time from surgery to death from any cause or to the last control date. Disease-free survival was defined as the time from surgery to first recurrence proven radiologically or histopathologically or the time from surgery to death.

Statistical Analysis

Statistical analyzes were performed using SPSS version 24.0. Continuous variables were expressed as mean ± standard deviation, and categorical variables as number (%). Visual histograms and analytical tests (Shapiro-Wilk test or Kolmogorov-Smirnov test) were used to test the normal distribution of continuous variables. Descriptive statistics were used for the analysis of clinical and pathological parameters between the two groups formed according to tumor location. Categorical variables were compared using the chi-square test or Fisher’s exact test. The independent samples t-test was used to compare the means of continuous variables with normal distribution between the two groups, or the Wilcoxon test when normal distribution was not met. Kaplan-Meier method was used for overall survival and disease-free survival analysis. Univariate and multivariate Cox regression analyses were used to determine independent predictors of overall survival and disease-free survival. A multivariate Cox regression model was created using parameters with p<0.05 in univariate analyzes. For all analyzes, a p value less than 0.05 was considered significant.

Results

Male to female ratio was significantly higher in left CC compared to right CC (M/F: 2.2 and 1.1 respectively, p=0.005). There was no significant difference between the two groups in terms of mean age and body mass index. The number of ASA II patients in the left CC group and the number of ASA III patients in the right CC group were higher (p=0.04). Laparoscopic surgery was performed in 78% of the patients in the right CC group and in 83.5% of the patients in the left CC group (p>0.05). The operative time was significantly longer in the left CC group compared to the right CC group (157±59 minutes and 142±53 minutes, respectively, p=0.02) (Table 1). Right hemicolectomy was performed in 126 (81.3%) patients, extended right hemicolectomy in 21 (13.5%) patients, and subtotal colectomy in 8 (5.2%) patients in the right CC group. Anterior resection was performed in 116 (66.3%) patients, left hemicolectomy in 55 (31.4%) patients and extended left hemicolectomy in 4 (2.3%) patients in the left CC group.

The mean number of harvested lymph nodes was significantly higher in the right CC group than the left CC group (32±3 and 27±9, respectively, p=0.001). There was no difference between the two groups in terms of lymph node metastasis (right CC: 46.4% and left CC: 45.7%). While there was no difference between the two groups in terms of the rates of TNM stages, it was determined that there were significant differences in terms of histological type and differentiation (Table 2). In the left CC group, 93.1% of the cancers were adenocarcinoma and 6.9% mucinous adenocarcinoma, while in the right CC group, 74.8% of the cancers were adenocarcinoma, 17.5% mucinous adenocarcinoma and 7.7% medullary carcinoma (p=0.001). While the poor differentiation rate was higher in the right CC group, the well differentiation rate was higher in the left CC group (p=0.04). Except that vascular invasion was more common in the left CC group, no difference was found between the two groups in terms of other prognostic factors (Table 2). Mean tumor diameter and tumor volume were also significantly higher in the right CC group (p=0.01 and p=0.002, respectively).

As a result of the median follow-up period of 54 months, it was determined that the 5-year overall survival and disease-free survival in the right CC group in stage I-III patients were worse (Figure 1, 2). When the survival analysis was performed according to the stages, although the 5-year overall survival and disease-free survival rates were lower in the right CC group compared to the left CC group in stage I and II patients, no statistically significant difference was found. However, the 5 year overall survival and disease-free survival rates were found to be statistically significantly lower in the right CC group compared to the left CC group in stage III patients (overall survival rate was 66.9% in right CC group and 81.8% in left CC group, p=0.03; disease-free survival rate was 54.2% in right CC group and 70.6% in left CC group, p=0.04) (Table 3, Figure 3, 4).

In the univariate analyzes performed in terms of the effect of prognostic factors on survival, it was found right CC, the presence of lymphatic, vascular and perineural invasion and the large tumor diameter had an effect on survival. In multivariate analyzes; it was found that advanced age, poor differentiation, tumor perforation, presence of tumor deposits, and large tumor volume significantly and negatively affected survival (Table 4).

Discussion

The proximal and distal parts of the splenic flexure are two different colon sections of which embryological origins are not the same.³ In CC, the location of the primary tumor creates clinical, pathological and genetic differences.^3,4 Changes in molecular features may also cause this difference.^15,16 It has been reported that microsatellite instability-high (MSI-H) ratio is significantly higher in the right CC and that it affects the treatment of stage II patients.^15,17 BRAF mutation is also a poor prognostic factor associated with peritoneal carcinomatosis, which is more common in the right CC.^18,19,20

In studies comparing two different tumor locations, it was reported that there were clinicopathological differences in right CC such as not very pronounced symptoms, higher rate of T4 stage, higher rate of poor differentiation and more common mucinous adenocarcinoma and medullary carcinoma, and female predominance.^21,22 In the left CC, on the other hand, more pronounced symptoms, lower stage and chromosomal differences were observed.^22,23,24 Although the reason for these changes between the two colon segments is not fully understood, different embryological origins are probably the most important factor.²⁵ In our study, female/male ratio, rate of poor differentiation, and rate of medullary carcinoma and mucinous adenocarcinoma were higher in right CC than left CC in accordance with the literature. In addition, tumor diameter was larger and tumor volume was higher in the right CC compared to the left CC.

However, a clear conclusion could not be reached in studies comparing the two groups in terms of survival. Many authors have stated that the prognosis of the right CC is worse.^11,26,27 However, some studies have reported that the right CC has a better prognosis.^9,12,13 Weiss et al.¹³ reported in their survival analysis in 53,801 patients with stage I-III CC that there was no difference in terms of prognosis between right and left CCs when all stages were included and also only in stage I disease. In the same study, it was reported that right CC had a better prognosis than left CC in stage II disease [hazard ratio (HR)=0.92; 95% confidence interval (CI): 0.87-0.97; p=0.001)]; while in stage III disease, right CC had a worse prognosis (HR=1.12; 95% CI: 1.06-1.18; p=0.001).¹³ In a study conducted by Warschow et al.¹² in more than 90,000 patients, 5-year overall survival in the right CC in stage I and II patients (in stage I disease, 77.4% in right CC and 74.9% in left CC; in stage II disease; 68.3% in right CC and 63.9% in left CC) and cancer-specific survival (In stage I disease, 94% in right CC and 91.7% in left CC; in stage II disease; 84.6% in right CC and 80.1% in left CC) were reported to be better. In the same study, the prognosis in stage III patients was similar in both groups (overall survival; 53.3% in right CC and 52.9% in left CC, cancer-specific survival; 63.6% in right CC and 64.6% in left CC).¹² In the study conducted by Yang et al.⁹ in 57,847 patients, it was stated that the right CC had better cancer-specific survival in stage I and II patients, but it was worse in stage III patients. In a meta-analysis performed by Petrelli et al.²⁸, 66 studies were included and it was found that left CC had a better prognosis (HR: 0.82; 95% CI: 0.79-0.84; p<0.001), and the location of the tumor was reported to be a prognostic criterion. In a study conducted by He et al.²⁹ in 377,849 patients, it was stated that liver and lung metastases were more in the left CC, but the prognosis was better than in the right CC. In addition, there are studies showing that complete mesocolic excision technique has a positive effect on prognosis, especially in right CC, as well as studies reporting that it does not affect prognosis.^30,31,32,33 In our study, while there was no statistically significant difference in terms of overall survival and disease-free survival in stage I and II patients, both overall survival and disease-free survival rates were statistically significantly worse in stage III patients with right CC compared to left CC patients.

There are some limitations in interpreting the results of this study. The first of these is the retrospective feature of the study. The genetic or molecular characteristics of all patients could not be examined and a comparison could not be made in this direction in terms of the two groups. MSI has been routinely evaluated in pathological examinations since 2015, but MSI could not be included in the comparison since this examination could not be performed in patients in the first years of the study. In addition, the fact that adjuvant chemotherapy protocols vary over the years and according to the oncologist is another limitation.

Conclusion

As a result, there might be clinicopathological and prognostic differences in CC depending on the location of the tumor. At the end of the long follow-up period in our series, it was found that, the prognosis in right CC was worse especially in stage III patients. We anticipate that the data obtained as a result of our study should be taken into account by the medical oncology department that we work together, in the selection and application process of adjuvant oncological treatments.

Ethics

Ethics Committee Approval: Retrospective study.

Informed Consent: Written consent was obtained from all patients for surgery.

Peer-review: Internally and externally peer review.

Authorship Contributions

Surgical and Medical Practices: S.Z., B.G., U.C., Ç.B., E.S., E.B., D.B., Concept: S.Z., B.G., E.B., D.B., Design: S.Z., U.C., D.B., Data Collection or Processing: S.Z., B.G., Ç.B., E.S., Analysis or Interpretation: S.Z., U.C., E.S., Literature Search: S.Z., B.G., Ç.B., Writing: S.Z., U.C., E.B., D.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.