Numerous recent studies have indicated an increase in the incidence of colorectal cancer among young adults, and the clinical characteristics of patients with early-onset CRC differ from those with late-onset CRC. However, to our knowledge, this study thoroughly analyzed the clinical, pathological, and molecular features of early-onset CRC patients in China. According to our study, in early-onset CRC patients, the proportion of men and women was nearly equal; in late-onset CRC patients, the males took a slight predominance, which was in accord with the other research[33, 39]. In contrast to our findings, early-onset CRC patients were more common in men than in women[40, 41]. Regarding the tumor location, patients with early-onset CRC typically have tumors in the distal colon and rectum, according to the relevant research[9, 31, 35, 36]. Whereas our study showed that the difference had no statistical significance in tumor location between the two types of CRC, the proportions of tumors on the right and left sides and rectal tumors were almost equal among both age groups, which was similar to other findings[42, 43]. The researchers found that in early-onset CRC patients, the right-sided tumors were more likely to be mucinous adenocarcinomas and signet-ring cell carcinomas when compared to left-sided tumors[44]. However, our research did not find a significant difference in early-onset CRC patients. Those divergent results may indicate that the pathogenesis of early-onset CRC in China was different from the other countries.
In our study, we discovered that early-onset CRC patients had a more advanced disease stage than late-onset CRC patients, which was consistent with the findings reported by other institutions[30–35]. In a retrospective study, 61.8% vs 46% of patients with advanced stages of early-onset CRC and late-onset CRC, respectively[34]; in another study, 253 patients with early-onset CRC and 232 patients with late-onset CRC accounted for 72% vs 63% of patients with advanced cancer, respectively[35]. Our research also revealed that patients with early-onset CRC were more likely to present with poorly differentiated and had more mucinous or signet-ring tumors than late-onset CRC patients, which was consistent with the previous results[45, 46]. Early-onset CRC patients had more advanced disease stages, poorly differentiated, and more mucinous or signet-ring tumors, which were seen in early-onset CRC patients, indicating unfavorable tumor biology and worse oncological prognosis.
Compared to late-onset CRC patients, the median and mean duration of symptoms were much longer in early-onset CRC patients, consistent with the other findings[35, 47]. The case-control study showed that the median time to treatment from symptom onset in rectal cancer was 217 days for patients under the age of 50, compared to 29.5 days for individuals above the age of 50[47]. A lack of knowledge of colorectal cancer-related symptoms in patients with early-onset CRC, a low rate of early screening, and the unwillingness of certain patients to seek medical care may contribute to the delay in diagnosis in early-onset CRC patients. We found that the delayed diagnosis had no direct relationship with why there was more advanced disease stage in early-onset CRC patients. Previous works demonstrated that the delayed diagnosis did not have a negative influence on the stage of the disease at presentation[47], and it could not be easily explained why there were more advanced disease stages in the early-onset CRC patients[35]. Conversely, according to the other studies, the delay in diagnosis might be one of the reasons that cause the increased proportion of patients diagnosed with advanced cancer[48, 49]. More work needs to be done to reveal the reasons for the two different results.
Our study found that in early-onset CRC patients, only a few of them be diagnosed with CRC by colonoscopy screen. In 2018, the American Cancer Society (ACS) changed the recommended age for those at average risk to begin screening from 50 to 45 years [50]. The recommendation is based on disease burden and results from microsimulation modeling studies[51]. In China, the guidelines recommended that individuals over 50 years old (50–75) and at average risk have a CRC screening[52]. In our younger cohort, the average age at diagnosis was 42. Lowering the screening age for young individuals with average risk may help prevent and identify early-onset CRC, which is beneficial for prevention and early detection. If early-onset CRC prevention were successful in young adults, it would have a considerable impact[53]. However, with the China's large population and restrained healthcare resources, we should carefully consider whether we need to readjust the starting age of screening for people at average risk. In our study, about 45.0% patients with intestinal bleeding as the chief presenting symptom in early-onset CRC patients. In the appropriate situations, it may be reasonable to consider a colonscopy in younger patients with persistent hematochezia, especially in regions with limited resources[35]. Future research needs to focus on age-stratified characteristics, and a microsimulation model is required to guide future screening strategies and decrease the disease burden.
In our study, we found no differences in the percentage of patients who got or did not get chemotherapy for early- and late-onset CRC patients. However, the study showed that individuals with early-onset CRC patients got 2–8 times more sessions of postoperative systemic chemotherapy than late-onset CRC patients[54]. Interestingly, according to the research, the prognosis of patients with early-onset CRC who received more chemotherapy was equivalent to or worse than those with late-onset CRC who received less therapy[32, 34, 55–57]. Thus, for patients with early-stage early-onset CRC who are considered low-risk, considerable consideration should be made to whether they should receive neoadjuvant or adjuvant treatment. Previous research has shown that APC mutations were related to poor colorectal cancer prognosis; in patients with early-onset CRC, APC, BRAF, and KRAS mutations were rare, which may explain the difference in treatment response between two types of CRC patients[58–61]. Furthermore, further research is required to understand the molecular process of early-onset CRC completely, so therapeutic care techniques may be designed particularly for these patients to enhance their prognostic outcome and overall survival.
According to our results, the d-MMR tumors were more common in early-onset CRC than in late-onset CRC, and in addition, the d-MMR tumors were more common in the left-sided colon and rectum in early-onset CRC. Other studies have shown that the incidence of d-MMR is around 20% in patients with early-onset CRC, compared to less than 15% in all colorectal cancer patients[62, 63]. Previous research has indicated that a family history of colorectal cancer is substantially connected with an elevated risk of early-onset CRC; around 30% of patients with early-onset CRC had a colorectal cancer family history[62–64]. There is evidence that increased genetic risk factors, such as familial adenomatous polyposis (FAP) or Lynch syndrome, are linked to an increased prevalence of early-onset CRC[65, 66]. Even though hereditary susceptibility is significant in EOCRC, it can not explain the observed increase in incidence rates[67].
In conclusion, early-onset CRC has distinct epidemiology, pathophysiology, and molecular characteristics compared to late-onset CRC in China. The preclinical symptoms, family history, and genetic features linked with early-onset CRC should be known to clinicians to aid in the diagnosis of young patients with colorectal cancer and to improve their disease prognosis. Further study is needed to understand better the pathophysiology of early-onset CRC and why there is a difference between the two types of CRC.