Early-onset colorectal cancer in patients younger than 50 years: a systematic review of the literature

Ilektra D. Kyrochristou^a, Georgios D. Lianos^a, Gerasimia D. Kyrochristou^a, Vaia Georvasili^a, Vasileios Tatsis^a, Michail Mitsis^a, Dimitrios Schizas^b, Konstantinos Vlachos^a

University Hospital of Ioannina, Greece; National and Kapodistrian University of Athens, Greece

^aDepartment of Surgery, University Hospital of Ioannina, Greece (Ilektra D. Kyrochristou, Georgios D. Lianos, Gerasimia D. Kyrochristou, Vaia Georvasili, Vasileios Tatsis, Michail Mitsis, Konstantinos Vlachos); ^b1^st Department of Surgery, National and Kapodistrian University of Athens, Greece (Dimitrios Schizas)

*equal contributors

Correspondence to: Ilektra Kyrochristou, MD, MSc, Department of Surgery, University Hospital of Ioannina, Ioannina, Greece, e-mail: electra.cyro@gmail.com

Received 11 March 2025; accepted 15 May 2025; published online 25 June 2025

DOI: https://doi.org/10.20524/aog.2025.0977

Abstract

Early-onset colorectal cancer (EO-CRC) refers to CRC diagnosed before the age of 50. Its incidence has risen in recent years, turning researchers’ attention to its oncologic behavior and potentially modifiable risk factors. In this review, PubMed/MEDLINE database was searched for all original research articles concerning EO-CRC. The inclusion criteria were CRC patients under 50, without a known predisposing factor for malignancy or an inherited CRC syndrome, presenting oncological characteristics and outcomes. All studies were assessed for bias, based on the ROBINS-E 2022 tool, and were synthesized in a qualitative analysis. Twenty-nine articles, reporting on 64,376 EO-CRC patients, were included in the qualitative synthesis. Results were classified into 3 categories: a) demographics; b) histopathologic characteristics; and c) treatment outcomes. Of these publications, 21 studies agreed that rectum (45%) and left-sided (47.1%) cancers are most common in younger patients, and 5 indicated that the highest prevalence of CRC concerns the 40-49 years age group. Seventeen of 29 studies reported a higher stage (III and IV) on diagnosis, with lymphovascular and perineural invasion. Our review has some limitations: as it was based on a single database, not all studies provided information on the variables; and patients were not categorized in all studies in the same age groups, although all were under 50 years. As EO-CRC is on the rise, the need for closer monitoring and possibly earlier screening becomes apparent. Further research should focus on finding novel screening biomarkers and modifiable risk factors that would decrease mortality and improve patient outcomes.

Keywords Early-onset colorectal cancer, young adults, guidelines, 50 years old

Ann Gastroenterol 2025; 38 (4): 364-379

Materials and methods

The PubMed/MEDLINE database was searched using the query string “colon cancer AND young adults AND 50 years” from 2004-2024. The search aimed to identify all articles on EO-CRC treatment outcomes. The research was conducted on 30^th August 2024 by 2 independent researchers (IK and GK), and any selection conflict was resolved by a third researcher (GL). Data were extracted in an Excel sheet and proofread by the 2 above independent researchers; the third resolved disagreements.

Inclusion criteria for our selection included articles concerning CRC patients aged under 50 years, reporting large-scale statistics on the prevalence and incidence of EO-CRC (on at least a nationwide scale), histopathological characteristics and oncological outcomes, including the response to adjuvant and neoadjuvant treatment.

Overall, 29 articles met the criteria and were included in the qualitative synthesis. The researchers’ algorithm is presented in Fig. 1.

Figure 1 PubMed algorithm of search

CRC, colorectal cancer

The main variables of the review were the prevalence and incidence of EO-CRC, histopathological characteristics, such as tumor location, tumor type, microsatellite instability status (MSI), TNM stage, lymphovascular and perineural invasion, and distant metastasis, and finally treatment outcomes after curative surgery and/or systemic therapy.

The review was structured according to the PRISMA checklist, which can be found in Supplementary Table 1. All studies were assessed for bias, based on the Risk of Bias In Non-randomized Studies of Exposure (ROBINS-E 2022) tool (Table 1, and Supplementary Tables 2, 3), and were then synthesized into a qualitative analysis.

Table 1 Risk of bias based on the ROBINS-E-2022 tool

Regarding risk factors for CRC, the PubMed database was also used to identify articles focusing on EO-CRC risk factors. The authors selected the ones they thought most representative, as they provided clinical data and evidence on all the factors they proposed. Their results, as well as comments on the hypothesized mechanisms of action for each risk factor, are presented in this article.

All outcomes are presented as percentages of the whole sample for each article, while the treatment outcomes are presented in terms of overall survival (OS) and disease-free survival (DFS), using relative risk (RR) and odds ratio (OR) to assess the response to treatment.

Results

Overall, 486 articles were published during this period relating to EO-CRC. Three hundred articles were excluded as irrelevant judged by their title. Of the remaining articles, 23 were excluded as they were review articles, 3 duplicates were found, and 5 more articles were excluded as they were in languages other than English (Spanish and Portuguese).

Ninety-three more articles were excluded after the abstract screening, as 20 examined only the racial disparities of EO-CRC, without providing sufficient information about the histopathological characteristics or the treatment outcomes of the individuals included, and the rest were irrelevant to the topic of the current review, as they were merely reporting small scale statistics that could not be interpreted in the review.

Ultimately 62 articles were full-text reviewed, of which 33 were excluded because they described only racial disparities (n=8), did not provide sufficient information (n=19), did not differentiate the age group of interest (n=5), or finally as they contained only molecular characteristics (n=1).

Finally, 29 articles were included in the synthesis, as presented in Fig. 1. All articles concerned EO-CRC, some referring to patients younger than 40 years. All articles are presented in Table 2, along with their primary and secondary outcomes.

Table 2 Articles about EO-CRC epidemiology and research outcomes

EO-CRC demographics

Overall, 135,126 patients were included in the synthesis. Sex information was provided in 23 of the 29 studies, specifying 43,945 (52.69%) male and 39,459 (47.31%) female patients.

Siegel et al [2] conducted one of the biggest research projects on OECRC epidemiology in the United States, reporting that its incidence in 2020 was 17,930 new cases and that these younger patients demonstrated a mortality rate of 7%, significantly lower than the 25% seen in older patients. In a 20-year study of the incidence of CRC, whereas an overall decrease in the number of cases was observed, the incidence of EO-CRC demonstrated a rise of 1.3% annually during the study period [4]. This steady surge of EO-CRC implies a significant environmental influence on its genesis, especially as almost all researchers agreed that there was no significant genetic predisposition for cancer in the populations included [2,4,7-9,11-12].

Loomans-Kroop et al [14], presenting a large series of 37,138 patients, further focused on the incidence of right and left-sided colon cancers in younger patients, concluding that patients under the age of 50 more often have distal colon tumors or rectal tumors. These results are in line with those of other researchers [2,6,28], who reported that left-sided colon cancer is the most frequent type in young patients, followed by the rectum.

Moreover, the incidence of EO-CRC seems to increase with the patient’s age. More specifically, Kim et al [12] reported a prevalence of colorectal neoplasia, in individuals undergoing colonoscopy, of 5.9% in the 20-29 years group, compared to 9.5% in the 30-39 years group. Other researchers concluded that the incidence of EO-CRC is much higher in the 40-49 years group than in younger patients [3,4,12,14], thus highlighting a need to bring forward the age of screening from 50 to 40 years.

EO-CRC histopathological characteristics

As previously stated, the majority of EO-CRC tumors are in the distal colon and rectum, even though a small increase in right-sided tumors has been noticed in the past 5 years [2]. The tumors do not demonstrate high MSI (6% for EO-CRC vs. 8% for patients aged >50 years) [4]; however, patients younger than 30 years are more likely to have tumors with high MSI compared to their older counterparts [29]. Additionally, no differences were detected concerning the K-RAS mutation profile [4].

There is a great deal of clinical data to suggest that EO-CRC is diagnosed in advanced stages, mostly in stage III, and that young patients present more frequently with larger tumors (T3 and T4) that have lymphovascular and/or perineural invasion, and even distant metastases [6,8,10,16,18,23,24,26]. Among the researchers, Da Silva et al presented the highest percentage of late-stage EO-CRC, with 75% of their EO-CRC patients being stage III or more [23]. Overall, the studies reported almost 15-25% of patients presenting with distal metastasis [8,13,18], more often in the liver, lung and other sites. Rodriguez et al [10] proved that more lymphatic metastases and deeper invasion of the intestinal wall were positively correlated with age, as patients under the age of 40 presented in their vast majority (88%) with T3 or T4 tumors, while 58% of them had already nodal metastasis. Park et al supported this observation, that EO-CRC was associated with a higher affected lymph node load, with 30.6% of patients being N2 [13].

Most of these young patients are symptomatic for more than 3 months, but because of their young age they compensate for their symptoms by self-caring, and they do not seek help until it is too late. It is very representative that, according to Siegel et al [2], a patient younger than 40 years is twice as likely to be diagnosed with advanced disease (stage III or IV) than his/her older equivalent.

Data also suggest that younger patients’ cancers are more likely to be mucinous or signet-cell type [18,26,30], although Shelleler et al [20], in a series of 244 cases, suggested otherwise. Moreover, younger patients tend to have tumors of higher grade than those older than 50 years, which are more often characterized as poorly differentiated or undifferentiated [18,25]. These histopathological characteristics constitute the elements of a more aggressive tumor type and explain the higher cancer-specific mortality of younger patients. All results regarding the histopathological characteristics of EO-CRC are presented in Table 3.

Table 3 EO-CRC histopathological characteristics

EO-CRC treatment outcomes

As patients <50 years of age usually present in advanced disease stages [2,4,6-13,16,18,23-26,29], one might expect that they would have worse treatment outcomes. However, this does not seem to be the case, as younger and older patients show comparable results in terms of OS and DFS [2,9,13,18,20,27,30]. Numbers varied for OS 65-87% for the younger and 68-91% for the older patients. Another thing worth mentioning is that patients younger than 40 years demonstrated a 5-year OS of 68%, significantly better than their older counterparts (P=0.03) [6]. However, Lipsyc-Sharf et al [17] reported that patients <35 years old demonstrated a slightly shorter progression-free survival of 9.33 months, vs. 10.55 months in older-onset CRC individuals (P=0.68).

Overall, the cancer-specific mortality rates are higher for EO-CRC patients, notably 28.7% for patients <50 years compared to 18.4% for older patients (P=0.014), demonstrating the more aggressive tumor behavior in the younger group [15,16]. Readmission and reoperation rates, as well as perioperative mortality, were comparable for all age groups.

Finally, researchers reported that young patients were more likely to receive systemic chemotherapy, even in the setting of overtreatment. Interestingly, Manjelievskaia et al [9] reported that young CRC patients were 2-8 times more likely to receive adjuvant chemotherapy after surgery (almost 70% of the enrolled individuals). As both those investigators and Kneuert commented, the 18-39 years group was even more likely to receive multi-agent regimens (mainly oxaliplatin or irinotecan based), rather than single-agent regimens [7]. This excessive therapy, however, did not seem to have any benefit in terms of OS or DFS, as the treatment gain appeared to be nil for stage II (RR 0.90, 95% confidence interval [CI] 0.69-1.17), and marginal for stage III (RR 0.89, 95%CI 0.81-0.97) and stage IV (RR 0.84, 95%CI 0.79-0.90) [7,9,17,22,27].

In a study of 6708 patients, Arhin et al [19] reported a statistically significant OS benefit from both primary tumor resection (PTR) and metastasectomy (hazard ratio [HR] 0.34, 95%CI 0.31-0.37; P<0.001) compared to palliative therapy only. Moreover, they demonstrated that patients undergoing PTR or metastasectomy alone also had better OS compared to those undergoing palliative care (HR 0.46, 95%CI 0.43-0.49; P<0.001, and HR 0.64, 95%CI 0.55-0.76; P<0.001, respectively). Their results highlight the significance of surgery in younger patients, taking into consideration that their better overall health and lack of comorbidities may distinguish them from older ones. All results on EO-CRC treatment outcomes are presented in Table 4.

Table 4 EO-CRC treatment outcomes

All articles were assessed for their risk of bias based on the ROBINS-E-2022 tool. Twenty-four were assessed to have a low risk of bias or minor concerns. Most risks of bias concern patient selection and the lack of control of the post-exposure interventions. More specifically, most research was retrospective, thus highlighting that some background checks of the patients regarding, for example, their genetic status may not have been accurate or may have been missing. The ratings of each article are presented in Table 1.

EO-CRC risk factors and their proposed mechanisms of actions

After looking at the increased incidence of EO-CRC, we quickly realized that most cases are diagnosed in advanced stages, as stated above. Thus, all treatment modalities can only achieve a medium survival rate. In this context, we thought it was important to address any potential (and most importantly modifiable) risk factors (Table 5).

Table 5 Risk factors of EO-CRC and their proposed mechanism of action

To begin with, increasing age seems to affect CRC prevalence even in patients younger than 50 years old, with the incidence rates being higher in the 40-49 years group than those aged 30-39 years [2].

Furthermore, adopting the western diet has led to the massive consumption of processed foods, especially processed meat, which is a great source of sulfur. The sulfur microbial diet has been identified as an EO-CRC risk factor, as H₂S seems to degrade the intestinal mucosa and cause chronic inflammation. These changes create a perfect microenvironment for the genesis and development of cancer [31].

Other risk factors associated with diet appear to be sweetened drink beverages and alcohol consumption, with the latter being the most important, as acetaldehyde has several proven genotoxic effects and leads to gut dysbiosis, where the reactive oxygen and nitrogen species injure the intestinal wall [32,37].

Inflammatory bowel disease has also been proposed to increase the risk of EO-CRC, with researchers highlighting various epigenetic changes, such as CpG island hypermethylation. This chronic inflammation is identified as an “oxyradical over-load” state, which stimulates some of the major carcinogenic pathways, such as the APC/tumor suppressor gene/CIN pathway, the MSI pathway, and the CIMP pathway [33,34]. However, genetic factors, such as somatic genetic mutations and clonal expansion noted in the IBD patients’ genome, may also lead to distinct cell populations of the colon becoming more widely distributed over time and occupying wider zones of the mucosa. Consequently, some dysregulated subclones of these cells grow at the expense of the normal surrounding epithelium, resulting in a malignant environment where CRC grows and expands [34].

In this context of an altered intestinal environment, changes in the gut microbiota seem to play a crucial role in the genesis and progression of cancer, with the increase of “bad” microbes (e.g., the Bacteroidaceae species) at the expense of protective ones [38].

In addition, metabolic syndrome—and especially obesity—have been accused of being promoters of EO-CRC, as insulin resistance has been implicated in triggering immune cell response and promoting tumorigenesis [35,36,41].

Last but not least, smoking has been identified, by almost all researchers, as a major risk factor for CRC in young patients. Several smoke carcinogens are well-known today: nitrosamines, benzene, heterocyclic amines and polycyclic aromatic hydrocarbons. Their effects on normal DNA include CpG methylation, the cause of the B-Raf gene (BRAF) mutation, and the activation of the oncogenic MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinases) pathway [40].

Discussion

EO-CRC is defined as colorectal cancer that occurs before the age of 50 years. Even though the global prevalence of CRC has tended to decrease over the last decades, EO-CRC seems to be on the rise [2,3] Interestingly, CRC is the leading cause of cancer incidence and mortality among individuals aged <50 years in America [42]. On the other side of the ocean, the incidence of EO-CRC in England has also continued to increase over the past 50 years, as Exarchakou et al report, with a distinct rise in cases of rectal cancer among patients younger than 50 years (the incidence was 5.2% in 1993 and had risen to 19.4% by 2014) [43].

The elevated disease risk in the generations born after 1950 is called the birth cohort effect. This phenomenon refers to the strong correlation of an outcome, such as incident CRC, with the year of birth. Currently, CRC incidence has been increasing rapidly across successive generations, particularly among millennials. A possible explanation could be epigenetic changes caused by gene–environment interactions, which result in somatic mutations and cancer generation [44]. Several other factors may also have contributed, such as the adoption of a western lifestyle, involving the consumption of processed foods and alcohol, as well as smoking [31,36,40].

EO-CRC is also more frequent in men than in women, although most researchers do not report significant differences in cancer risk between the sexes [2-4,11-12]. Socioeconomic status is also commented on in several articles, with farmers demonstrating a higher incidence than white-collar laborers, and uninsured patients having a greater risk of EO-CRC, diagnosed in an advanced stage [7,11].

What seems interesting is the reference to serum 25-hydroxivitamin D as a risk factor and a potential screening tool for EO-CRC. In a study conducted in an Asian population, Kim et al reported in 2023 that the HR for CRC in patients demonstrating elevated 25-hydroxivitamin D levels (>20 ng/mL) was 0.41 (95%CI 0.27-0.63), while for levels between 10 and 19 ng/mL it was 0.61 (95%CI 0.43-0.86), indicating that vitamin D might have a protective role against the appearance of CRC. Moreover, lower vitamin D levels were associated with more invasive tumors. These observations led them to suggest that vitamin D could be a useful screening biomarker of patients at risk of CRC development, as it could be measured easily [45].

These results showing the vitamin’s protective role on EO-CRC are further supported by a recent meta-analysis of the risk factors of early onset CRC [46], which demonstrated a pooled OR of 0.72 (95%CI 0.56-0.92). The patient sample in this study also included an Italian population, even though the majority of patients were again Asian.

The proposed mechanism is that of angiogenesis inhibition and suppression of cell proliferation, even though a recent experimental study in mice demonstrated that vitamin D supplementation led to increased production of Carnobacterium maltaromaticum, a metabolite of vitamin D, which seems to have protective action against the occurrence and progression of CRC [47].

Despite their different biological behavior, EO-CRC and common CRC do not show significant differences in OS and DFS, as described above. Younger than older patients tend to receive adjuvant chemotherapy; however, this overtreatment does not affect survival rates. Younger adults also receive a combination of chemotherapeutic drugs rather than a single agent, although this multi-agent therapy does not appear to be superior to the traditional one [7,9].

What only seems to be different among the younger and the older age groups is the time needed for the diagnosis and initiation of treatment. More specifically, according to Castelo et al, after the initial doctor’s visit (which already is delayed for most EO-CRC patients) it takes on average 4.3 days longer to diagnose an EO-CRC, compared with a CRC in the over-50s detected on a routine screening control. However, the younger patients start their treatment 4.5 days sooner than older ones [48]. All these slight differences do not affect treatment success or survival, further underlining the need for better screening, as the goal would be to diagnose an asymptomatic young adult with CRC and not wait until he seeks medical care.

The current systematic review has some limitations. Firstly, the synthesis was based on results only found in one database (PubMed/Medline). Secondly, given the different age classifications of patients under 50 (e.g., in groups of 20-29, 30-39 and 40-49), it is not possible to draw overall conclusions with accuracy. We hope that the current presentation of the existing data will help future researchers in their research planning so that they may enhance our cumulative results.

This review has not been registered in any national or international registry. The research and the original draft were structured according to the PRISMA guidelines [49]. No funding was available for the conduct or publication of the current paper, and the authors declare no competing interests.

Concluding remarks

As the prevalence of CRC among individuals younger than 50 years increases, the need for a better understanding of its biology and response to treatment becomes more direct than ever. Young patients present in stages more advanced than older ones, thus implying that the screening program for CRC detection should change and start at an earlier age.

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Notes

Conflict of Interest: None