Early-onset colorectal cancer: a retrospective study of demographic, clinicopathological, and molecular characteristics in China

Abstract

Background: The global incidence and mortality rate of early-onset CRC has gradually increased. The clinicopathological features and pathogenesis of early-onset CRC were still not fully elucidated, and relative data were lacking in China. This research aims to examin the demographic, clinicopathological characteristics of early-onset CRC in China.

Materials and methods: This retrospective study included 509 patients who were diagnosed with colorectal cancer from 2019 to 2021 in the General Surgery Department of the Second Xiangya Hospital, Central South University.

Results: Early-onset CRC patients had significantly longer median symptom durations (90 vs 60 days, P < 0.001). There was no direct relationship between the symptoms duration and the stage of the disease at presentation in early-onset CRC patients (p = 0.750). Early-onset CRC patients showed a more advanced disease stage than late-onset CRC patients (65.7% VS 52.9%, P = 0.005). Additionally, early-onset CRC patients were more likely to have poorly differentiated (30.2% vs 16.7%, p = 0.001), mucinous or signet-ring tumors than late-onset CRC patients (22.4% vs 15.0%, P = 0.048). The d-MMR tumors were more common in early-onset CRC patients (15.9% vs 5.8%, P < 0.001). There was no significant difference in age, gender, BMI, or pathology between patients with right- and left-sided CRC in early-onset CRC patients.

Conclusions: Early-onset CRC has different epidemiology, pathology, and molecular features compared to late-onset CRC in China. More research is required to understand better the pathophysiology of early-onset CRC and why there are different characteristics between the two types of CRC.

Introduction

Colorectal cancer is the third most common malignancy and the second leading cause of cancer mortality globally, patients who died from colorectal cancer accounted for 9.4% of all cancer-related fatalities[1]. The overall incidence of colorectal cancer has stabilized or declined, primarily due to the popularization of colonoscopic screening[2]. However, the incidence and mortality rate of colorectal cancer in patients younger than 50 (early-onset CRC) gradually increased around the world[3–6]. Early-onset CRC is the second most common form of malignancy in this age group and the third leading cause of cancer-related death in the United States, with at least one in ten newly diagnosed colorectal cancer patients being diagnosed with early-onset CRC[7, 8]. The incidence of early-onset CRC was different in various regions of the globe. In the United States, between 2000 and 2013, early-onset CRC incidence rates rose by 22%; the mortality rates declined by 34% for colorectal cancer in patients older than 50 (late-onset CRC), whereas increased by 13% for early-onset CRC[9]. In Europe, between 2004 and 2016, the average annual percentage change in the incidence of early-onset CRC in patients aged 20–29 years was 7.9%, 4.9% for patients aged 30–39 years, and 1.6% for those aged 40–49 years[10].

Despite the global trend of an aging population, by 2030, around 11% of colon cancers and 23% of rectal cancers will occur among people under the age of 50 years[11]. It was unknown why the incidence and mortality of early-onset CRC were increasing. There has previously been evidence that specific early-life exposures, such as a Westernized diet[12, 13], increased stress[14, 15], excessive antibiotic use[16, 17], altered gut microbiome[18–21], smoking[22], obesity[23–26] and prolonged sitting[27], were associated with an increased risk of developing early-onset CRC. There were mounting pieces of evidence that nutrition, numerous drugs, and environmental factors may all contribute to cellular epigenetic changes that result in certain tumor molecular subtypes[28, 29]. Previous studies have shown that early-onset CRC patients had different features from late-onset CRC patients that the tumor tended to present at an advanced stage and often exhibited poor histopathological features[30–35]. The distal colon and rectum are the most common locations for early-onset CRC tumors[9, 31, 36].

With the increasing prevalence of early-onset CRC, we must have a better understanding of early-onset CRC traits and differences to make accurate strategies for disease early prevention, diagnosis, and therapy. According to the research, geographic features and socioeconomic variables such as race, family income, and education degree were associated with a greater incidence and mortality of early-onset CRC[37]. In addition, there were substantial regional differences of early-onset CRC in the tumor site, gender features, and survival[38]. While the pathogenesis, clinicopathological, and molecular characteristics of the early-onset CRC have been widely studied in Europe and the U.S, there was not a sufficient amount of comparable data in China. Thus, to fill this information vacancy, this research aims to examine the clinical, pathological, and molecular features of early-onset CRC patients in China to investigate these characteristics in more detail, which will aid in the disease's early prevention, diagnosis, and therapy.

Materials And Methods

Patients and information collections: The patients who were diagnosed with colorectal cancer in the General Surgery Department of the Second Xiangya Hospital, Central South University, from 2019 to 2021. We performed retrospective research on all patients < 50 years old at the time of CRC diagnosis and a random sample of patients ≥ 50 years old. We collected the following information: (1) patient characteristics: gender, age at diagnosis, body mass index (BMI), tumor location, clinical symptoms, family history; (2) symptom duration; (3) the tumor stage (according to the American Joint Committee on Cancer, AJCC 8th edition), the number of metastatic lymph nodes; (4) pathological information: histological type, grade of tumor differentiation, perineural and (or) vascular invasion; (5) microsatellite instability status. We excluded patients with appendiceal tumors, carcinoma in situ, carcinoid tumors, and incomplete records.

Definitions

EOCRC was defined as being diagnosed before the age of 50, because this is when most national screening programs begin. (1) Clinical symptoms were defined as intestinal bleeding, abdominal pain, change in bowel habits (number of daily stool changes, constipation, diarrhea), bowel obstruction, others (anemia, imaging abnormalities, abdominal mass, abdominal distension…), colonoscopy screen. For patients with multiple initial symptoms, we selected as the chief presenting symptom the symptom that prompted the diagnosis. (2) Symptom duration was calculated using the patient's self-reported duration of the primary presenting symptom at the time of the first visit. Symptom duration was set to zero days for individuals discovered by chance. (3) Tumor stages III and IV were defined as advanced disease stages. (4) Right-sided colon tumors were defined as tumors arising at the cecum, ascending colon, hepatic flexure, and transverse colon (not including the splenic flexure). Left-sided colon tumors were defined as tumors arising at the splenic flexure, descending colon, and sigmoid colon. Left-sided CRC tumors including left-sided colon tumors and rectum. (5) We defined MMR-deficiency (dMMR) tumors as a lack of expression of at least one mismatch repair (MMR) protein shown by immunohistochemistry.

Results

Demographic characteristics: This study included 509 patients diagnosed with CRC from 2019 to 2021. Patient demographics are summarized in Table 1. The patients were divided into two categories, and our analytic cohort had 180 early-onset CRC patients and 329 late-onset CRC patients. The median age at diagnosis was 41.81 ± 7.2 years for early-onset CRC patients and 63.25 ± 7.8 years for late-onset CRC patients. In terms of gender, females accounted for 51.7% and males for 48.3% in early-onset CRC, whereas in late-onset CRC, 37.4% of patients were female and 62.6% were male (P = 0.002; Table 1). Late-onset CRC patients had higher BMI compared with the early-onset CRC patients (mean: 23.82 ± 3.01 vs 22.84 ± 3.02 kg/m2), moreover the late-onset CRC patients were more likely to be overweight (32.2% vs 19.4%, P = 0.002; Table 1). Our study showed no differences in the percentage of patients who got or did not get chemotherapy for early- and late-onset CRC patients (41.7% vs 41.0%, P = 0.890; Table 1).

Symptoms and symptoms duration

There were no significant differences in presenting symptoms between two age groups; intestinal bleeding was the most common chief presenting symptom in both age groups. About 2.8% of patients were detected due to colonoscopy screens in early-onset CRC patients, while about 7.6% were in late-onset CRC patients (p = 0.027; Table 1). Compared to late-onset CRC, the median symptoms duration was significantly longer in the early-onset CRC (90 days [IQR 30–180] vs 60 days [IQR 20–150], P < 0.001; Table 1), and the mean symptoms duration was likewise longer in the younger patients (164.1 ± 213.1 vs 92.3 ± 108.2, P < 0.001; Table 1). There was no direct relationship between the symptoms duration and the stage of the disease at presentation in early-onset CRC patients (median days, 90 [IQR 30–180] vs 90 [IQR 60–180]; mean days, 167.1 ± 236.6 vs 156.3 ± 164.0, p = 0.750; Table 2).

Clinical And Pathological Features

In early-onset CRC patients, there were 17.8% for right-sided colon cancer and 33.9% for left-sided colon cancer, compared to 19.8% and 33.7% in late-onset CRC patients, respectively (Table 1). Besides, early-onset CRC patients had more rectum cancer than late-onset CRC patients (48.3% vs 46.5%; Table 1). However, the difference had no statistical significance in tumor location between the two types of CRC (P = 0.851; Table 1). Early-onset CRC patients had a more advanced disease stage compared with late-onset CRC patients (65.7% VS 52.9%, P = 0.005; Table 1). About 41.0% and 24.7% of early-onset patients had stage III and IV disease stages, respectively, compared to 38.3% and 14.6% in the reference group(Table 1). The early-onset CRC patients also had higher rates of lymph node metastatic versus the late-onset CRC patients (52.8% vs 47.4%, P = 0.041; Table 3). Early-onset CRC patients were more likely to present with poorly differentiated than late-onset CRC patients (30.2% vs 16.7%, p = 0.001; Table 1). Besides, the younger patients also had more mucinous or signet-ring tumors than the reference group (22.4% vs 15.0%, P = 0.048; Table 1). Otherwise, there was no significant difference in the perineural invasion and vascular invasion between early-onset and late-onset CRC (33.5% vs 32.7%, P = 0.851; Table 1).

Immunohistochemistry Features

For immunohistochemical features analysis, we only had access to 44 patients; some MMR gene deficiencies contained several proteins. The d-MMR tumors were more likely to be seen in early-onset CRC than in late-onset CRC patients (15.9% vs 5.8%, p < 0.001; Table 1). In early-onset CRC patients, the d-MMR tumors mostly happen in the left-sided colon and rectum compared to late-onset CRC patients, who were more likely to happen in the right-sided colon (69.2% vs 33.3%, P < 0.05; Table 1). Early-onset CRC exhibited a higher prevalence of MLH1 and PMS2 germline mutations than later-onset CRC in d-MMR tumors (69.2% vs 38.9%, 61.5% vs 44.5%; Table 4).

Features of Right- Versus Left-Sided Early-Onset CRC

The majority of early-onset CRC was left-sided, with the rectum (58.8%) and sigmoid colon (28.4%) accounting for the majority of this group, followed by the splenic flexure and descending colon (12.8%)(Table 5). About 75.0% of the right-sided early-onset CRC patients were in advanced disease stage, while 63.7% of the left-sided early-onset CRC patients were; however, the difference was not statistically significant (P = 0.222; Table 5). Otherwise, there was no significant difference in age, sex, BMI, pathology, or whether to receive chemotherapy between right- and left-sided early-onset CRC.

Discussion

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.

Declarations

Acknowledgements 

No applicable.

Authors’ contributions

Zongyao Chen and Weidong Chen conceived the study and wrote the manuscript. Shuangya Deng and Xiaoxin Jin analyzed the dats. Yuhang Liu and Wang Xiao collected the data andclinical information. Weidong Chen was involved in the final editing. All authors approved the final manuscript.

Funding 

No available

Availability of data and materials 

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics stetements

Studies involving human subjects

Generated Statement: The studies involving human participants were reviewed and approved by Clinical Research Ethics Committee of the Second Xiangya Hospital, Central South University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Inclusion of identifiable human data

Generated Statement: No potentially identifiable human images or data is presented in this study.

Consent for publication

Written informed consent was obtained from the patient for the publication of this report and any accompanying images.

Author details

Department of General Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, PR China.

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