Worrisome Trends in Young-Onset Colorectal Cancer: Now Is the Time for Action

Abstract

Colorectal cancer (CRC) in the young adult population is of increasing incidence and concern. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge of CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Young-onset CRCs are characterized by more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left-colon sided location of the primary tumor. Genetic predisposition and heritable syndromes contribute to this trend, but perhaps more concerning is the majority of new diagnoses that involve no traceable genetic risk factors are sporadic. This review provides a summary of key aspects related to colorectal cancer in young adults, including epidemiology, etiology, genetics, clinical difficulties, early diagnosis, and prevention with emphasis on screening age.

Introduction

Colorectal cancer (CRC) is a heterogeneous disease of the colon and rectum predominantly arising from adenomatous polyps or adenomas. Assessing incidence and mortality, three distinct global temporal trends were described in the most recent decade: (a) increasing incidence and mortality (Baltic countries, Russia, China, and Brazil); (b) increasing incidence but decreasing mortality (Canada, the UK, Denmark, and Singapore); and (c) decreasing incidence and decreasing mortality (the USA, Japan, and France) [1]. Lifestyle determines approximately 57.2% and 50.2% of incident CRCs in men and women, irrespective of age. Thus, there is a great opportunity to reduce risk across the population via lifestyle modifications. However, age is one of the most important risk factors for CRC, and evidence supports that it might be considered the most powerful predictor of CRC [2].

While CRC has long been considered a disease of older adults, recent data suggest an increasing incidence of young-onset CRC (yCRC), which has largely been defined as adults younger than 50 years of age. In 2019, Lui et al. extracted cancer incidence data from the International Agency for Research on Cancer (IARC) and reported significant increased risk of yCRC for 11 out of 12 countries, with annual percent change in incidence (APCi) ranging from 0.32 (95% confidence interval [CI], 0.01 to 0.64) in Italy to 9.20 (95% CI, 6.85 to 11.59) in Brazil [3]. Over the last decade in the UK (between 2005–2007 and 2015–2017), bowel cancer age-standardized incidence rates for females and males combined decreased by 4%. In females age-standardized incidence rates decreased by 2%, and in males rates decreased by 6%. Lifestyle factors and increased healthcare use among their population is major reason for this outcome [4]. Fortunately, there are well-established screening guidelines that allow for the prevention and early detection of CRC in such countries. However, existing CRC screening guidelines do not sufficiently address a newly emerging high-risk group: young-onset CRC. Recent estimates indicate that sporadic CRC accounts for approximately 70% of yCRCs. Studies have shown that yCRCs have increased by 2.8–36.5% globally over the last several decades; however, this is not suggestive of increasing incidence of hereditary CRCs [5–7]. The increasing use of colonoscopy for diagnostic and screening purposes may have been responsible for a proportion of the detected CRCs in young adults. Nevertheless, detection bias is probably not the driving factor for this trend, since young adults are less likely to be screened for CRC [8].

The incidence of CRC in India is lower than that in the Western countries. Several individual studies on Indian and Bangladeshi patients have consistently documented a relatively high proportion of young age CRC, with a mean age of around 40–45 years. Interestingly, many of the reports on young age CRC in India came from West Bengal, a state in the eastern region of India [9–11].

Young adults (ages 18–35) form the major bulk of living generation in India. Mortality from yCRC has likewise increased by 11% in the period 2005–2015 (SEER data). This has made CRC a serious threat to this young population, and it is the most commonly diagnosed and the most common cause of cancer death among men younger than 50 [12]. Because of the slow progression from adenoma to adenocarcinoma, screening programs reduce CRC risk by detecting and removing adenomas and increase survival and cure rates by earlier diagnosis. Despite the recommendations issued by the United States Preventive Services Task Force (USPSTF) and the American Cancer Society, adherence to these guidelines remains low in India despite national efforts to improve screening rates.

Definition of Age Groups

An unequivocal definition of “young adult CRC” is currently needed, as no clear and widely accepted consensus is available in literature or guidelines. According to a non-pediatric oncology definition, the definition generally comprises all CRCs diagnosed before the screening age, i.e., < 50 years of age. Most screening programs start from this age chosen based on cost-effective analyses of health care systems sustainability [13]. As definition of age groups among CRC patients is currently based on non-specific epidemiological, screening, or clinical trial accrual criteria, these age groups subdivision is indeed a limitation for interpreting results obtained from published molecular and clinical studies among yCRCs.

Molecular Etiology, Hereditary Syndromes, and Familiarity

In the general population of CRC, there are three main pathways of carcinogenesis involved in the onset and development of CRC: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). These mechanisms of carcinogenesis are not mutually exclusive and may coexist. A small proportion of MSI-CRCs can also present with CIN, while around 50% of MSS-CRC are CIN negative [14]. The latter subgroup has been defined as microsatellite and chromosome stable (MACS). These tumors are more frequently rectal or left-sided characterized by a poor prognosis and poorly recognized by the immune system.

A prominent cause of yCRC is the presence of a germline oncogene mutation, giving rise to a hereditary cancer syndrome. Prevalence of hereditary CRC syndromes among yCRCs is influenced by the different age groups analyzed in different studies, with the higher prevalence among patients < 35 years old [15].

These potential scenarios should be considered among yCRCs:

1. Germline genetic predisposition: Pathogenic germline mutations associated with major hereditary cancer syndromes account for a distinct subset of patients with yCRC. Although this proportion is approximately 2 to 5% of all patients with CRC, it increases to approximately 16 to 20% when considering patients with CRC between the ages of 18 and 50 years and can be as high as 35% among patients with CRC between ages 18 and 35 years [16]. Hereditary CRC syndromes that share a polyposis phenotype include classic and attenuated familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, polymerase proofreading–associated polyposis, and NTHL1-associated polyposis. Familial adenomatous polyposis is driven by a germline mutation in the APC gene that clinically translates into the formation of numerous intestinal adenomas. MUTYH-associated polyposis and NTHL1-associated polyposis are derived from germline mutations in the MYH and the NTHL1 genes, respectively [17]. Germline mutations in the tumor suppressor genes STK11 and LKB1 cause Peutz-Jeghers syndrome, whereas those in SMAD4/BMPR1A lead to juvenile polyposis syndrome. Polyps associated with the latter syndromes are characterized by hamartomatous rather than adenomatous histology. Patients with polymerase proofreading–associated polyposis carry rare germline mutations in the POLE and POLD1 genes, which encode for proofreading regions of DNA polymerases that lead to the development of multiple colorectal adenomas and yCRC [18]. Lynch syndrome is the most common hereditary CRC syndrome, arising from germline mutations that cause deficiencies in the native DNA mismatch repair mechanisms. Other subsets of patients who develop yCRC may harbor elevated genetic risk without a well-defined pathogenic germline mutation. Some patients present with clinical suspicion for Lynch syndrome and CRC with microsatellite instability yet lack pathogenic germline mutations in a mismatch repair gene. These individuals are defined as having mutation-negative Lynch syndrome or Lynch-like syndrome [19]. Finally, a family history of CRC in at least one first-degree relative is associated with a 2.24-fold (range, 1.55–2.80) increased risk for CRC.

2. Somatic genetic mutations: As mentioned above, three major pathways of CRC carcinogenesis have been described: chromosomal instability, microsatellite instability, and CpG island methylator phenotype. Approximately 70% of sporadic CRC results from CIN pathway. It follows adenoma-carcinoma sequence and involves various genes including APC, TP53, KRAS, and MYC. yCRCs exhibiting chromosomal instability arise primarily in the proximal colon, in contrast to later-onset chromosomal instability–associated CRCs, which tend to be located in the distal colon. Although microsatellite instability is the key feature of Lynch syndrome, a specific subset of yCRC is characterized as microsatellite-stable and chromosome-stable CRCs and has an anatomic predilection for the distal colon and rectum. Microsatellite-stable and chromosome-stable tumors are biologically aggressive, with tendencies toward early metastasis and recurrence [14, 20]. Another subset of yCRC is associated with CpG island methylator phenotype low status and presents with a positive family history and a predominance of left-sided tumors.

3. Non-hereditary and non-familiar yCRC: It is very surprising to notice that although hereditary cancer syndromes and familiarity are more frequent among young individuals, half of yCRC patients have neither hereditary cancer syndrome nor familiarity. This implies that, since these patients are not included in screening programs, they are often diagnosed in later stages of the disease. Among this subset of patients, without known hereditary cancer syndromes, different alterations in TNFR1, EIF4E, LTBP4, CYR61, UCHL1, FOS, and FOS B genes have been demonstrated between early- and late-onset CRC [15, 16]. However, definite conclusions are still far to be obtained.

4. Sporadic yCRC: Although environmental and lifestyle habits such as red meat consumption and sedentary lifestyle are established risk factors for CRC in general, their specific contributions to yCRC have yet to be established. The worrisome trends leading to yCRC include consumption of fast food which has increased three- to five-fold among children and young adults; obesity, type 2 diabetes mellitus, and metabolic syndrome which is increasingly affecting younger adults [21]. An environment of chronic tissue inflammation has also been associated with malignant transformation. A subset of yCRC arises in association with underlying inflammatory bowel disease such as Crohn colitis and ulcerative colitis [22]. The role of the colon microbiome in colon carcinogenesis is a novel area of active investigation. Pathobiotic bacteria can promote CRC through chronic inflammation with accumulation of DNA damage in epithelial cells. Emerging evidence suggests that Fusobacterium nucleatum may be enriched in right-sided CRCs. It is capable of upregulating the expression of oncogenic and proinflammatory genes, and its detection in tumor tissue has been prognostic of OS. However, whether a unique microbiome milieu is associated with yCRC remains unknown [23, 24].

Clinical Difficulties with yCRC

Avoiding delay in diagnosis of yCRC is an urgent challenge for all health care providers. Given the limited role of CRC screening among asymptomatic young adults, the majority of yCRCs are diagnosed after symptomatic presentation [25]. Young adults tend to wait longer than older adults between symptom onset and presentation (up to 6.2 months) and also experience further delays until treatment initiation compared with older adults [26]. This is mainly due to low level of suspiciousness by clinicians and also a sense of invincibility in young adults. In 61% of patients < 50 years, CRC is diagnosed as stage III or IV, strikingly different from older CRC patients (46–50% of stages III–IV). yCRCs are more frequently poorly differentiated G3 tumors with normal CEA levels predominantly involving left-sided colon and rectum. Signet ring cell CRC, accounting for < 1% of all CRC, among younger patients account for 3–13% of cases, especially in those younger than 30 years [27]. Given factors such as underinsurance and hesitancy to seek care among the younger population, a high degree of suspicion and expeditious diagnostic workup of the symptomatic patient are crucial to help decrease the disproportionate late-stage presentations of yCRC.

Prevention and Early Detection

Risk factor modification and screening have been credited as the largest contributors to the overall decline in CRC mortality. Because risk factors specific to yCRC remain to be elucidated, current prevention recommendations for yCRC have not significantly differed from those for later-onset disease. Due to slow progression from adenoma to adenocarcinoma, a substantial proportion of CRC cases and deaths might be preventable. Increased understanding of the oncogenesis and development of screening technologies has supported the implementation of CRC screening in clinical practice and public health programs. Screening programs reduce CRC risk by detecting and removing adenomas and increase survival and cure rates by earlier diagnosis [28]. Most individuals are counseled to start screening at 50, unless family history supports an earlier start. However, adherence to CRC screening is often suboptimal, especially among ethnic minorities [29, 30].

Screening of patients with a higher than average risk of CRC due to hereditary CRC syndromes, serrated polyposis syndrome, and other high familial CRC risk should be referred in the following situations:

1. A family history of colorectal cancer:

2. A family history of one first-degree relative diagnosed with CRC under 50 years, or

3. Two affected first-degree relatives diagnosed with CRC at any age.

4. A patient with personal history of CRC diagnosed under age 50 years (early-onset CRC).

5. A patient with a personal history of CRC diagnosed at any age, who also has a first-degree relative diagnosed with CRC at any age.

6. Patients with multiple polyps, specifically: patients under 60 years of age with at least 10 adenomas, or patients from 60 years of age with at least 20 adenomas or at least 10 adenomas and a family history of CRC or polyposis.

7. Patients with known or suspected inherited CRC predisposition syndromes including:

8. Lynch syndrome

9. Polyposis syndromes including serrated polyposis syndrome (SPS) and familial polyposis.

For the surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection, evidence-based guidelines have been formulated by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI), and Public Health England (PHE). The key recommendations for future colorectal cancer (CRC) following polypectomy comprise either:

1. two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or

2. five or more premalignant polyps.

This cohort should undergo a one-off surveillance colonoscopy at 3 years. Post-CRC resection patients should undergo a 1-year clearance colonoscopy, then a surveillance colonoscopy after 3 more years [31].

Is Lowering the Age for CRC Screening Need of the Hour?

Advanced-stage diagnosis and mortality from yCRC are increasing, and it has been urged that it is time to take action. CRC is becoming a health threat for young adults, especially because it is often diagnosed in advanced stages. In fact, incidence has increased mostly for metastatic disease. Data from the National Health Interview Survey (2015) revealed that 45% of 50–54-year-old adults have undergone screening colonoscopy, compared to only 17.8% of those aged 40–49 years. Since the intrinsic risk in the 45–49 age group is likely closer to that in the 50–55 age group than apparent, and this might support extending the age for screening. Selected groups of people are known to be at increased risk for CRC, including inflammatory bowel disease patients (relative risk 2.6–2.8) and hereditary cancer gene carriers. However, the proportion of yCRC attributable to these diseases is relatively small, and most yCRCs are sporadic; thus, interventions are needed for the general population. Only one in six individuals with yCRC has an inherited predisposition to cancer, while the other five have the same risk factors as the general population [32]. Seventy-five to eighty percent of all yCRC belong to the average-risk population, and they would benefit from screening.

Years of potential life lost (YPLL) is an estimate of the average years a person would have lived if he or she had not died prematurely. Measuring the impact of disease in terms of YPLL, this young population is severely compromised. This has been shown very recently by Chen et al. They analyzed the YPLL of a hypothetical unscreened 50-year-old German population and inferentially extended the analysis to a younger 45-year-old cohort. Their data support earlier screening: preventing a younger person from CRC occurrence and death spares more future productive years, and this is more heavily weighted in the analysis, as opposed to simply counting deaths. In the scenario of repeated colonoscopies, the proportion of prevented YPLL declined with delayed screening, while extending the age of screening below 50 proved useful in maximizing YPLL prevention [33].

The expected benefits and harms of screening from 45 years of age have also been estimated by three separately developed simulation software programs. The Cancer Intervention and Surveillance Modeling Network (CISNET) employed three simulations (SimCRC, CRC-SPIN, and MISCAN-Colon) to predict the optimal ages of start, ages of stop, intervals, and methods of screening. The outcomes of these studies were expected benefits (life-years gained, LYG, an estimate of the number of years of life gained compared to no screening) and expected risks (burden of colonoscopies) for each combination of age of start, age of stop, and interval [34]. Only two of these models initially supported starting colonoscopies at the age of 45 years (SimCRC and CRC-SPIN). However, after noticing some bias in MISCAN-Colon, the American Cancer Society (ACS) requested the analysis to be rerun and finally all models unanimously supported starting colonoscopy at the age of 45 years. Computational models also have several limitations. They assume an unrealistic 100% adherence rate and also failed to consider CRC as a multifactorial disease where other risk factors influence one’s risk (i.e., sex, diabetes, diet, lifestyle, and others). Overall, the most important message of these studies is that screening should be recommended before the age of 50 years, or even as early as at 40 years, in the majority of simulated scenarios. Therefore, screening at 45 years appears to be not only a robust screening option, but also a potentially conservative one.

Model data are supported by real data from the SEER: of all YPLL from CRC in 2010–2014, 10% came from the 45–49 age group and another 13% from the 50–54 age group. Young individuals combined (45–54 age group) account for almost a quarter of the overall CRC burden. Thus, YPLL and mortality from CRC could be drastically reduced by using 10-year (or less) intervals of colonoscopy from the age of 45 years in men and 47 years in women [33].

Current Guidelines

Some scientific societies have started to explore and recommend screening from 45 years of age. In May 2018, the American Cancer Society (ACS) initiated a qualified recommendation for average-risk adults to begin screening at 45 years [35]. The results of this approach are much awaited in terms of the number needed to diagnose a case and number needed to save a life. Previous recommendations by the ACS were based on joint analysis of risks by ACS, United States Preventive Service Task Force (USPSTF), and American College of Radiology (ACR) in 2008 [36]. Since 2008, evidence has accumulated on the changing risks of CRC. In fact, the annual percentage change in the incidence rate for adults aged 40–49 years is twice that of the 50–54 age group in recent years [37]. Moreover, 2008 recommendations prioritized mortality reduction over incidence reduction, unlike the 2018 edition.

The American College of Gastroenterology (ACG) and the American Society of Gastrointestinal Endoscopy (ASGE) have started to support colonoscopies from 45 years of age for non-white individuals [38]. Following ACS recommendations, some countries have adjusted their screening start age. For example, Germany has decreased the start age from 55 to 50 years, and England lowered the start age from 60 to 50 years. However, no country has recommended screening starting at the age of 45 yet. In 2016, the USPSTF determined that “for all modalities, strategies with screening beginning at age 45 years provided additional LYG at a lower number of additional colonoscopies than strategies with screening beginning at later ages” [34]. Ultimately, the USPSTF did not recommend starting at 45 because they judged the benefit to be modest and because one model (MISCAN) did not agree in the first edition. Correction of the assumptions beneath the MISCAN models then resulted in its agreement with the other two models. This might prompt the USPSTF to change their recommendations accordingly in the near future. Furthermore, a significant concern is how guidelines should be written. It stands to reason that they should be modeled after collecting solid experimental data from well designed and replicated clinical trials. Recommendations should avoid simulations as the level of evidence cannot be as valid. The ACS recommendation is mainly rooted in computational evidence, which might be accurate but could not reflect reality. Data on screening outcomes are scarce in this age group, and results from this recommendation are much awaited.

Conclusion

Many Western and Asian countries reported an increasing incidence and mortality in yCRC at an alarming rate in the last three decades, mainly for rectal cancers [39, 40]. This has sparked the debate on whether young adults could be better managed, and scientific societies engaged in argument in favor of or against lowering the age for screening colonoscopy. In the context of insufficient scientific evidence from population studies, more epidemiological studies are urgently needed to accurately describe the impact and burden of yCRC across countries. We recommend momentary adequate lowering of the age of first screening colonoscopy where the incidence of yCRC has been reported to be increasing, while clinical and research studies deepen our understanding of yCRC physiopathology and oncogenesis. Social awareness actions are indispensable to increasing adherence to the screening and also update in physician’s knowledge to face this new challenge. Younger populations should also be advised on healthier living and eliminating cancer-predisposing behavior. Incorrect alimentary habits and excessive sedentarity contributed to the increase in diabetes and obesity. Specifically, obesity has been recently associated with a higher risk for yCRC in young women [41].

Currently routine screening for CRC is not recommended in India due to several reasons including low incidence rates, availability of expertise, and low socio-economic status. Nevertheless, there are various studies including one conducted in Tata Memorial Hospital, Mumbai, which concludes saying that incidence of CRC is increasing in young population which show poor prognostic factors and are more advanced stage at presentation with a worse disease-free survival after surgery [39, 42–45]. It should also be noted that the population registries in India cover only 7.45% of the population, while worldwide cancer registries cover 21% of the population; so, some amount of under reporting may be possible in India. So, CRC screening in general should be stressed upon more in India and also the age of screening initiation should be lower than 50 years.

Lowering the age of the first colonoscopy is a major and needed approach. The young population is being increasingly afflicted by CRC and its threat to both life expectancy and quality of life. Previous recommendations were adequate for the twentieth century, but as population characteristics change, clinical recommendations must be adapted for optimal management. In light of the increase of yCRC incidence and mortality, it is imperative that actions are taken; an earlier screening from age 45 might reflect a desire to help reverse the morbidity and mortality of CRC in this population.

Declarations

Conflict of Interest

The authors declare no competing interests.