In recent decades, the diagnosis of EOCRC has increased significantly, imposing a greater disease burden on the patients. In contrast, the prevalence and mortality rates of LOCRC have either stabilized or decreased in numerous high-income countries, attracting considerable attention. Comprehensive studies comparing EOCRC and LOCRC patients across various stages, surgical procedures, and subgroups are lacking. The appropriate age for screening and survival outcomes of EOCRC patients are also unclear. In this study, we investigated the clinicopathological distinctions between EOCRC and LOCRC patients, assessed the impact of surgical approaches, MMR status, and TNM staging on survival, and analyzed the diagnosis age to determine the optimal screening age for CRC.
We analyzed the clinical characteristics of EOCRC and LOCRC patients. The results suggested that EOCRC patients exhibited a better nutritional status. They also showed a higher ratio of dMMR, along with a greater incidence of perineural and vascular invasion. These observations were similar to the findings of Gabriel et al. [21–23], who reported that EOCRC becomes more aggressive as the tumor stage advances. These changes might be attributed to advanced tumor staging that commonly occurs in EOCRC patients. In this study, the proportion of male patients was slightly higher. This disparity could be linked to variations in the intestinal microbiome, specifically, the presence of lower probiotics and higher oncogenic bacteria in men, which can increase their risk of developing CRC [24]. The incidence of CRC is correlated with androgen levels [25, 26], and mutations in the KRAS oncogene in male patients may increase the expression of the KDM5D gene on the Y-chromosome [27]. Other factors like smoking, alcohol consumption, and dietary habits may also contribute to this gender disparity. These findings highlighted the need to further investigate gender-specific factors related to the development of CRC.
We conducted a comparative analysis of rectal and colon cancers and found that the OS rates were similar in both groups. The patients with left-sided CRC exhibited better OS compared to those with right-sided CRC. Although the difference in OS between the early-stage EOCRC and LOCRC patients was not significant, EOCRC patients showed a significantly higher survival rate after five years. This trend occurred probably because EOCRC patients had a higher chance of completing the treatment regimen and receiving more intensive treatment. In the last decade, the number of EOCRC cases increased considerably, imposing a greater disease burden on the younger patient group.
The effect of surgical modalities on the survival of EOCRC and LOCRC patients was low. However, by comparing the groups based on surgical approach, we found that patients who underwent laparoscopic surgery showed a significantly higher survival rate than those who underwent open surgery, which matched the findings of other studies [28]. No significant difference was observed in OS between pMMR and dMMR patients in the EOCRC and LOCRC groups, although long-term survival was better for pMMR patients in the EOCRC group than in the LOCRC group. This difference in survival was not found among dMMR patients, probably because their sample size was smaller. The dMMR patients had higher OS than the pMMR patients. Some studies have found a significant prevalence of dMMR in EOCRC patients, with a longer five-year disease-free survival rate in the dMMR group than in the pMMR group [29, 30]. These findings highlighted the need for further research on the effect of the MMR expression status in EOCRC patients.
We also found that EOCRC patients generally presented with more advanced TNM stages at diagnosis compared to LOCRC patients. The incidence of advanced disease might be higher because patients with EOCRC are generally diagnosed after the onset of symptoms, resulting in a higher incidence of late detection [31], as shown by O'Sullivan et al. [32]. In contrast, because of regular screening practices, LOCRC patients are diagnosed at earlier stages. For TNM stages I and II, the survival rate of EOCRC patients was considerably higher than that of LOCRC patients. However, in stages III and IV, the differences in the survival rate were not significant. These observations emphasized the need for early screening in younger populations to enhance survival by diagnosing diseases at lower TNM stages. Current medical guidelines suggest that screening for colorectal cancer should begin at age 50; however, this approach overlooks younger at-risk demographics. In this study, we analyzed nearly 12 years of colorectal cancer data, encompassing 10,172 cases. The incidence rate of colorectal cancer in individuals under 30 years was relatively low at 1.93% but increased sharply after the age of 40, and reached 15.93% in the 40–50-year-old age group. Correspondingly, the age-proportional cumulative curve showed a significant increase in the number of patients who were 40 years old, marking a critical inflection point.
Zaborowski et al. emphasized the need for earlier screening and risk assessment for CRC, particularly for individuals at high risk [33, 34]. Studies have shown that the prevalence of young-onset adenoma is around 9%, and the prevalence increases with age. The risk for metachronous advanced neoplasia after diagnosis is around 6% [35], with a majority being disseminated cases of EOCRC. The U.S. Multi-Society Task Force (MSTF) on CRC recommends screening all relatives (≥40 years old) of CRC patients diagnosed before 60 years [36]. The 2023 CSCO guidelines suggested regular CRC screening from 50 years of age for those at average risk. Only about 20% of individuals diagnosed with CRC before 50 years carry a cancer-related genetic mutation [37]. After implementing standardized screening guidelines in the United States in 2000, the incidence and mortality of CRC decreased. This decrease is particularly noticeable among those who are 65 years old and older and undergo regular screening. In contrast, an approximate annual increase of 2% was found in the incidence of proximal, distal colon, and rectal cancers in individuals under 50. This increase was most pronounced in the 20–29-year-old age group [38]. A recent large-scale screening study in China involving nearly 100,000 residents suggested initiating screening for CRC at over 40 years of age [39].
Considering that some individuals may have additional risk factors, initiating CRC screening at 50 years may lead to more advanced disease stages and poorer prognosis. Because of the prevalent sedentary lifestyle and unhealthy diet, earlier screening for specific populations is advisable. We recommend that CRC screening should start at age 40 in the Chinese population, particularly for groups with a higher incidence of the disease or other risk factors. Lowering the screening age can reduce the tumor burden on EOCRC patients, which can decrease the incidence and mortality rates.
This study provided insights into the differences between EOCRC and LOCRC patients. However, it had certain limitations. First, as it was a retrospective cohort study, the partial lack of baseline patient information may have affected the precision of our interpretations. Second, as this was a single-center study, our findings may not fully represent other populations and cannot be used to analyze CRC incidence trends among patients over 40, based on demographic data. Additionally, the analysis of EOCRC patient subgroups was limited due to incomplete MMR testing and a relatively small sample size. Despite these limitations, our study provided important insights into the clinical characteristics of EOCRC patients and their differences from LOCRC patients, corroborated by other relevant studies. Our findings highlighted the importance of early screening of EOCRC patients to lower their TNM stage and improve survival outcomes.