Surgical resection and endoscopic submucosal dissection (ESD) are the main therapeutic for T1 CRC. Despite LN dissection during surgical intervention, 2.3–4% of T1 CRC patients still suffer from post-operative relapse [15]. Endoscopic resection of early-stage CRC including mucosal and submucosal cancer is advantageous, which could dramatically decrease postoperative morbidity, improves life quality, provide almost comparable long-term clinical outcomes compared with radical surgery[6, 16]. Notable, great caution should be given to endoscopic resection indications in T1 CRC in consideration of LNM in nearly one-tenth T1 CRC patients [17]. According to Japanese Society for Cancer of the Colon and Rectum (JSCCR)guideline, the presence of any of the four factors (lymphovascular invasion, budding, tumor invasion depth as well as poor histology) [18] indicates the recommendation of additional surgery for LN dissection. Except for its effect on prognosis, the benefit of surgical resection is limited, particularly for patients of advanced age or with severe comorbidities.
The risk factors for LNM were identified by logistic regression analysis. Patients with inadequate number of sampled LN were eliminated during selection process (the cutoff value was set at 12 on the basis that at least 12 LNs exams are generally required for precise pathological diagnosis [3]. In our study, LNM rate was 14.9 % (960 out of 6423), which was remarkably higher than previously reported in T1 CRC patients (about 10%) [17]. The inconsistency might be caused by our present inclusion criteria, that is, only patients receiving radical surgery were enrolled in our research. To further attenuate the risk of false negative LNM and downgrading after neoadjuvant chemoradiation, patients with inadequate LNs sampled and those undergoing preoperative radiotherapy were eliminated in our research, which could give rise to more reliable LNM rate than previous ones.
In the present population-based research, we comprehensively examined the predictors of regional LNM in T1 CRC patients undergoing surgery and having at least 12 LNs sampled. Histology, tumor grade, tumor size, CEA, race, primary tumor location and age were significant predictors for LNM. Mucinous carcinoma(MAC)and Signet ring cell carcinoma༈SRCC༉ are relatively rare pathological types of CRC, accounting for about 10–15% and 0.1–2.4% of all CRC cases, respectively [19]. As a distinct subtype, MAC and SRCC have been showed to be associated with higher risks of lymph node involvement in stage I and II colorectal cancer[20]. Here, we consistently showed higher LNM risk in patients with colorectal MAC and SRCC (OR = 1.695, 95%CI:1.286–2.235, P < 0.001 and OR = 2.006, 95%CI: 1.017–3.957, P = 0.045). In addition, the LNM risk was significantly lower in well-differentiated tumors than moderately or poorly differentiated or undifferentiated tumors. Consistent with previous findings in T1 rectal and colon cancer[21]. Furthermore, only tumor size ≥ 3 cm showed an elevated risk of regional LNM (OR = 1.316, 95%CI: 1.016–1.706, P = 0.038). Like other studies concerning colorectal cancer [21–23], Consistent with our discovered that tumor size was a predictive factor for the risk of LNM in T1 colorectal cancer.
Primary tumor site has long been demonstrated to influence LNM risk in CRC. However, the prognostic significance and LNM relevance of laterality in T1 CRC (mainly including left hemi-colon, right hemi-colon and rectum), has been explored, giving rise to controversial outcomes [24]. Therefore, the whole colorectal tract was divided into eight sections for to determine the possible correlation between tumor sites and diverse clinical variables. As a result, elder patients with rectum/rectosigmoid junction cancer had higher LNM risk than those with cecum cancer. The LNM risk in T1 rectal carcinoma has been showed to be as high as 15% [25, 26], declining to 8% in the left colon and 3% in the right colon [25]. Here, we report alike consequence, which suggests that carcinoma of the ascending colon is a significantly decreases the LNM risk, whereas rectum/rectosigmoid junction cancer significantly increases the LNM risk.
Consistent with previous results in T1 CRC [21], we also found older age as a significant negative predictor for LNM. To be specific, LNM risk of patients with 65–79 years and over 80 years declined to 0.63 and 0.47, respectively in comparison to those under 49 years (both P < 0.001). The survival of CRC patients is affected by diverse prognostic factors. Surgical resection, a major therapy for CRC, might be improper or unsafe for elderly patients with comorbidities. Instead, endoscopic resection has been proposed as a minimally invasive technique for precancerous lesions as well as early-stage CRC.
Survival analysis revealed that LNM was a significant prognostic indicator for CSS (HR = 1.755, 95%CI: 1.390–2.215, P < 0.001) but not for OS (HR = 1.063, 95%CI: 0.928–1.218, P = 0.380) in elderly patients. Meanwhile, LNE≥12 was a significant positive indicator for OS in comparison with LNE < 12 (HR = 0.834, 95%CI: 0.758–0.917, P < 0.001) but not for CSS. Nevertheless, after PSM adjustment, OS (HR = 0.904, 95%CI: 0.816–1.001, P = 0.052) or CSS (HR = 0.955, 95%CI: 0.772–1.181, P = 0.668) was not significantly different between LNE≥12 and LNE < 12 in. Moreover, univariate and multivariate Cox regression analyses also evealed tumor size, CEA level, race as well as marital status as significant indicators for OS and CSS.
In elderly tumor patients, various factors could cause the existence of right censoring, including loss of follow-up and no death, which do not prevent survival or death of patients. By contrast, when patients die from non-oncological causes during follow-up, the proportion of cause-specific death (CSD) is decreased. The application of right censored data using conventional regression survival analysis can lead to biases, generally causing overestimation of the possibility of CSD. Unfortunately, the above concern is frequently observed in prognostic prediction among the elderly, who are more vulnerable to frailty and comorbidities, and have elevated non-oncological death than other age group. Under this situation, competing-risk concept might be used to readily solve the problem[27]. For multivariate analysis, the two most commonly applied approaches include cause-specific hazard function and proportional subdistribution hazard function. The latter renders the covariant effects as better and more intuitive explanation, which can be properly used to calculate risk score and to construct clinical prediction model [28]. In terms of predictive factors, LNE≥12 was not significantly better than LNE < 12 (SHR = 0.891, 95% CI: 0.693–1.145 P = 0.37). Consistently with previous outcomes, we also find the negative correlation between tumor size ≥3cm and survival (SHR = 2.289, 95% CI: 1.388–3.776, P = 0.026), which is suggestive that tumor size could reflect tumor invasiveness to certain degree [29]. Furthermore,our study showed that Primary tumor site in rectum(SHR = 1.772, 95% CI: 1.204–2.607, P = 0.0037) were significant worse than cecum for elderly T1 CRC patients. It is correspond with the LNM risk in T1 rectal carcinoma higher than in the left colon or in right colon[25, 26].Preoperative CEA and histology have been prevalently accepted as independent prognostic indicators for CRC, capable of effective prognostic prediction in CRC. Positive CEA level and poorly differentiated histology are independent influencing factors for CRC prognosis. The prognostic value of these variables is also reflected in our model.
In this population-based research, our findings are mainly based on real-world outcomes. Nevertheless, certain limitations must be acknowledged, which are mainly caused by the intrinsic defects of SEER dataset. Lymphovascular invasion, submucosal invasion depth as well as tumor budding are also likely to affect LNM risk, which, are unavailable in SEER database. In addition, selection biases are unavoidable in the retrospective analysis.
In summary, in this population-based analysis on T1 CRC patients after surgery, the decreased morbidity for local excision has to be weighed against the favorable outcomes. Tumor size < 3cm, well/moderately differentiated, negative CEA level and adenocarcinoma could be used to select proper elderly colorectal cancer patients for Local excision.