Review Article

Colorectal cancer in adolescent and young adults: epidemiology

in Japan and narrative review
Ayako Ueno1, Mitsuru Yokota1, Masayuki Ueno2,3^, Kazuyuki Kawamoto1
1
Department of General Surgery, Kurashiki Central Hospital, Okayama, Japan; 2Department of Gastroenterology and Hepatology, Kurashiki Central
Hospital, Okayama, Japan; 3Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Contributions: (I) Conception and design: A Ueno, M Ueno; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV)
Collection and assembly of data: A Ueno; (V) Data analysis and interpretation: A Ueno, M Yokota; (VI) Manuscript writing: All authors; (VII) Final
approval of the manuscript: All authors.
Correspondence to: Masayuki Ueno, MD. Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Miwa 1-1-1, Kurashiki,
Okayama 710-8602, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Email: mu13951@kchnet.or.jp.

Background and Objective: Although only a small proportion of colorectal cancer (CRC) cases develop
in adolescents and young adults (AYAs), its incidence has increased recently. We aimed to conduct a narrative
literature review and summarize the epidemiology, clinicopathological features, genetics, and treatments for
AYA-CRCs.
Methods: We searched the articles published in the PubMed database until November 30, 2022, with
keywords, “((adolescent and young adult) OR AYA) AND ((colorectal cancer) OR (colon cancer) OR (rectal
cancer))” and “young-onset AND ((colorectal cancer) OR (colon cancer) OR (rectal cancer))”.
Key Content and Findings: In Japan, the annual incidence of AYA-CRC was approximately 1,200 in the
1970s, but has increased to 2,000 nowadays. An increased incidence of AYA-CRC has also been reported in
other countries. AYA-CRC tends to be a more advanced disease at presentation than CRC in older patients,
with more adverse histological features and variability in molecular characteristics. Diagnosis of CRC is often
delayed in AYAs because they are not invited to undergo cancer screening. Three to five percent of patients
with AYA-CRC have hereditary cancer syndromes such as Lynch syndrome and familial adenomatous
polyposis (FAP), and a family history should be obtained. Additionally, providing information on fertility
preservation and social systems before starting treatment is important for sustainable treatment and life after
cancer treatment.
Conclusions: The number of AYA-CRC cases is increasing in Japan. Before initiating treatment for AYA-
CRC, we should know that these patients may have a hereditary disease and fertility preservation should be
explained. More physicians should be aware of the importance of AYA-CRC.

Keywords: Adolescents and young adults (AYAs); colorectal cancer (CRC); hereditary cancer; epidemiology; screening

Submitted Feb 08, 2023. Accepted for publication Jun 26, 2023. Published online Jul 19, 2023.
doi: 10.21037/jgo-23-98
View this article at: https://dx.doi.org/10.21037/jgo-23-98

Introduction young adults (AYAs) (1). Colorectal cancer (CRC) is

In Japan, approximately one million people are diagnosed the most common cancer and the second leading cause
with cancer annually, 2% of whom are adolescents and of cancer-related death in Japan; more than 150,000

^ ORCID: 0000-0002-2497-9327.

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
Journal of Gastrointestinal Oncology, Vol 14, No 4 August 2023 1857

patients are newly diagnosed with CRC, and more than AU. No systematic review of the articles or meta-analysis
50,000 patients die from CRC every year (2). Among AYA was performed. The detailed methods are summarized in
individuals in Japan, CRC is the fourth most common cancer Table 1. Although the definition of AYA varies among
after breast, uterine, and thyroid cancers (3). The incidence reports (13), we used this term for individuals aged 15–39
of AYA-CRC is up to 2,000 patients per year, accounting unless otherwise specified.
for approximately 10% of all cancers diagnosed in this age
group (4). In Japan, healthy AYAs are not recommended
Epidemiology and clinical characteristics of
for cancer screening, except for cervical cancer (5). Cervical
AYA-CRC
cancer screening with cytology is recommended for women
aged 20 years or more, though the implementation rate is Epidemiology of AYA-CRC in Japan and other countries
reported to be low (6). Regarding CRC, a population-based
The incidence of AYA-CRC in Japan is increasing gradually,
screening program with annual immunochemical fecal
from 1,200 patients diagnosed with CRC in 1975 to 2,000
occult blood tests was started in 1992 as a national policy;
in 2015 (Figure 2A) (4). Increasing trends in AYA-CRC
however, this program only targeted people over 40 years have also been reported in other countries such as the
of age based on morbidity (7). Thus, it may be difficult to United States (14,15), Canada (16), England (17,18), and
diagnose AYA-CRC at the asymptomatic stage. In addition, Australia (19,20), and similar trends have been observed
failure to recognize or deny the importance of symptoms may worldwide (21). The Global Burden of Disease Study has
lead to a delayed diagnosis (8). A case-control study showed reported the global epidemiology of AYA-CRC; the global
that the median time from symptom onset to treatment was incidence of AYA-CRC had increased from 37,285 in
217 days in patients aged <50 years compared to 29.5 days 1990 to 76,090 in 2019 (22). Recent changes in lifestyles
in patients aged ≥50 years (9). In this article, we aimed to such as Western-style diet and physical inactivity are
review the clinicopathological characteristics, genetics, thought to have caused the increase of the incidence of
and management of AYA-CRC. Although there have been AYA-CRC (23). In the United States, one in 1,200 (0.08%)
a lot of excellent review articles about young-onset CRC individuals developed CRC at 40 years of age or younger
(10-12), most of them do not focus on the AYA population in the current era (24); in particular, the incidence of rectal
(15–39 years old). As far as we know, this is the first review cancer is increasing more rapidly than colon cancer (25).
article that highlights current situations of AYA-CRC By 2030, it is estimated that the incidence of CRC in
in Japan. We present this article in accordance with the individuals aged 20–34 will increase up to 90% for colon
Narrative Review reporting checklist (available at https:// cancer and 124% for rectal cancer (26). On the other
jgo.amegroups.com/article/view/10.21037/jgo-23-98/rc). hand, the incidence of AYA-CRC in Korea between 2011
and 2015 decreased slightly compared to those between
Methods 2006 and 2010 (27). A multinational cohort study in Asia
showed that the increasing trend of young-onset (including
We conducted an electronic search of articles in the PubMed 40–49 age group) was the most pronounced in male rectal
database published until November 30, 2022. Articles cancer (28).
related to AYA-CRC were identified using keywords, A Japanese multicenter cohort study showed a slight
“((adolescent and young adult) OR AYA) AND ((colorectal male predominance (56.8%) in the incidence of AYA-CRC
cancer) OR (colon cancer) OR (rectal cancer))”. We also with 54.4%, 23.7%, and 21.9% of tumors occurring in the
searched and reviewed articles related to young-onset CRC rectum, left colon, and right colon, respectively (29). A
using keywords such as “young-onset AND ((colorectal single-center study in Taiwan showed that >40% of AYA-
cancer) OR (colon cancer) OR (rectal cancer))”. Only the CRC cases were stage IV at diagnosis and <10% were
articles published in English were included. Articles without stage I at diagnosis (30). The mortality rate of AYA-CRC
abstracts, case reports, and articles without available full has decreased in Japan, and the annual number of deaths
text were excluded (Figure 1). When we searched literatures from CRC has decreased from 700 in 1975 to 250 in 2020
related to young-onset CRC, review articles were also (Figure 2B) (2). In the United States, on the other hand, the
excluded because there was a lot of overlap of information. mortality of AYA-CRC is still increasing (31,32). Disease
The entire text of the articles was reviewed and analyzed by stage at diagnosis is the most striking prognostic factor,

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
1858 Ueno et al. CRC in AYA

1. AYA-CRC 2. young-onset CRC

Records identified from PubMed Records identified from PubMed

(n=67) (n=213)
Identification

Search Terms #1: Search Terms #2:

“((adolescent and young adult) OR “young-onset AND ((colorectal
AYA) AND ((colorectal cancer) OR cancer) OR (colon cancer) OR (rectal
(colon cancer) OR (rectal cancer))” cancer))”

Reports excluded: Reports excluded:

• Abstract not available (n=3) • Abstract not available (n=26)
• Full-text not available (n=9) • Not written in English (n=1)
• Not written in English (n=3) • Case reports (n=7)
• Case reports (n=5) • Reviews (n=17)
Screening

• Lack of relevancy to AYA-CRC (n=14) • Duplicates of search #1 (n=2)

• No/few additional findings on AYA-CRC (n=147)

Articles included in review

Articles included in review
• Original articles (n=27)
(n=13)
• Review articles (n=6)

Figure 1 Literature search flow diagram. AYA, adolescent and young adult; CRC, colorectal cancer.

Table 1 The search strategy summary

Items Specification

Date of search 1 December 2022

Databases and other sources PubMed

searched

Search terms used #1 “((adolescent and young adult) OR AYA) AND ((colorectal cancer) OR (colon cancer) OR (rectal
cancer))”; #2 “young-onset AND ((colorectal cancer) OR (colon cancer) OR (rectal cancer))”

Timeframe Until 30 November 2022

Inclusion and exclusion criteria Inclusion: English language, abstract, and full-text available. Exclusion: case reports (#1 and #2)
and reviews (#2)

Selection process A Ueno reviewed and analyzed the extracted articles

whereas male sex, black genetic ancestry, no insurance, that the presence of a family history of CRC in first-degree
poorly differentiated histology, higher tumor grade, and relatives increases the risk of CRC by up to 4-fold (37).
exposure to fine particulate matter pollution have also been Understanding the risk factors for AYA-CRC can help
reported to be associated with worse survival (33-35). identify those who would benefit from CRC screening,
and AYAs with a family history may benefit from CRC
screening.
Risk factors for AYA-CRC
According to a recent systematic review, one prospective,
Family history of CRC may be an important risk factor for five retrospective, and one cross-sectional study investigated
AYA-CRC. Mork et al. retrospectively analyzed 193 patients the risk factors of young-onset CRC, five of which targeted
aged 35 years or younger and found that the family history the AYA population (38). Due to the rare incidence of
of CRC in first- and second-degree relatives was present in AYA-CRC, three studies investigated the risk factors for
11.9% and 32.1%, respectively (36). Another study showed adenomas or other neoplastic polyps and identified family

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
Journal of Gastrointestinal Oncology, Vol 14, No 4 August 2023 1859

A 1600 B 400
1400 Colon cancer 350

Number of patients
300
Number of patients
1200 Rectal cancer

1000 250
800 200
600 150
400 100 Colon cancer

200 50 Rectal cancer

0 0
1975 1980 1985 1990 1995 2000 2005 2010 2015 1975 1980 1985 1990 1995 2000 2005 2010 2015 2020
Year Year

Figure 2 Longitudinal change of estimated (A) annual incidence and (B) annual mortality of colorectal cancer in people aged 15–39 years in
Japan.

history of CRC, older age, male sex, obesity, less physical may be better than those of the general population with
activity, smoking, alcohol intake, and diabetes mellitus CRC (17,47).
as risk factors for neoplastic colonic polyps in AYAs Regarding genetic and molecular characteristics, Tricoli
(39-41). On the other hand, two studies assessed the risk et al. conducted a comprehensive study using whole-
factors for CRC or rectal cancer in AYAs and revealed exome sequencing and found that several mutations were
that family history of CRC, genetic ancestry other than significantly more frequent in AYAs with CRC than in
black or white, and inflammatory bowel disease were patients with CRC aged 61–90 years (48). McVeigh et al.
associated with a higher frequency of AYA-CRC (42,43). evaluated the genomic profile of AYAs with advanced solid
The risk factors and associated evidence are summarized in tumors and found that a considerable proportion of patients
Table 2. Kim et al. pointed out that several risk factors such as had targetable mutations (49). Salem et al. compared the
smoking, drinking, and less physical activity can be changed molecular profiles of right- and left-sided CRC in AYAs (50).
and maintaining good lifestyle habits would help prevent They found that mutations in MSH2 and MSH6, as well as
AYA-CRC (39). In a large cohort of female nurses aged the microsatellite instability (MSI)-high phenotype, were
25–42 years, higher intake of vitamin D was associated with more frequent in right-sided AYA-CRC than in left-sided
decreased risk of early-onset CRC; thus, vitamin D intake AYA-CRC (20.8% vs. 4.8%); clinical significance of MSH2/
may be encouraged in young women (44). MSH6 mutations and MSI-high phenotype is described in
the following section. Chemotherapy regimens for CRC
need to be tailored based on the MSI status; for example,
The difference in clinicopathological and molecular
adding oxaliplatin to fluoropyrimidine is recommended
characteristics between AYA-CRC and elderly CRC
as adjuvant therapy for MSI-high CRC (51), and immune
Several clinicopathological differences have been reported checkpoint inhibitors are recommended for stage IV MSI-
between AYA-CRC and CRC in elderly patients. Adverse high CRC (52,53). Therefore, MSI testing should be
histology is more common in AYA-CRC patients than considered for AYAs with CRC, especially those with right-
in older patients. In a Japanese multicenter study, 10.2% sided tumors. The consensus molecular subtype (CMS) is
of resected AYA-CRC cases had mucinous or poorly a recently developed classification system for CRC at the
differentiated histology (29). Another study from the gene expression level (54), and it has been reported that
United States revealed that 37% of patients with CRC aged CMS1 was the most common in the AYA age group (55).
<30 years had poorly differentiated tumors (45). According
to the Surveillance, Epidemiology, and End Results database,
Hereditary cancer associated with AYA-CRC
histopathological diagnoses other than adenocarcinoma
were more frequent in patients aged 15–19 (26.7%) than A l t h o u g h m o s t c a s e s o f AYA - C R C a r e s p o r a d i c ,
in those aged 35–39 (13.6%) (46). Although most AYA- approximately 30% are thought to have a hereditary
CRC cases are diagnosed at an advanced stage, the disease- component (37,56). While 3–5% of these have well-
specific and overall survival rates are comparable to or characterized hereditary cancer syndromes such as

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
1860 Ueno et al. CRC in AYA

Table 2 Risk factors for CRC or neoplastic colorectal polyps in AYAs

Risk factors Description Reference

Family history Family history of CRC was associated with an increased risk of NCP (OR, 13.28; 95% CI: 5.70–30.97) (40,43)

Family history of CRC was present in 27% (17/62) of patients ≤30 years old with CRC

Age Age over 30 years was associated with an increased risk of colorectal adenoma (OR, 2.37; 95% CI: 1.64–3.42) (39-41)

Higher age was associated with an increased risk of NCP (OR, 1.11; 95% CI: 1.07–1.15)

Higher age was associated with an increased risk of NCP in young adults aged 30–39 years (OR, 1.09; 95%
CI: 1.08–1.11)

Male sex Male sex was associated with an increased risk of NCP in young adults aged 30–39 years (OR, 1.37; 95% (39)
CI: 1.27–1.49)

Race Race other than black or white was associated with an increased risk of rectal cancer in AYAs (OR, 1.46; (42)
95% CI: 1.23–1.73)

Obesity Higher BMI was associated with an increased risk of NCP (OR, 1.07; 95% CI: 1.03–1.12) (39,40)

Obesity was associated with an increased risk of NCP in young adults aged 30–39 years (OR, 1.26; 95% CI:
1.19–1.34)

Less physical Regular exercise was associated with decreased risk of NCP in young adults aged 30–39 years (OR, 0.89; (39)
activity 95% CI: 0.81–0.97)

Smoking Current smoking status was associated with an increased risk of colorectal adenoma OR, 1.48; 95% CI: (39,41)
1.14–1.91

Current or former smoker was associated with an increased risk of NCP in young adults aged 30–39 years
(OR, 1.29; 95% CI: 1.21–1.38)

Alcohol Alcohol consumption was associated with an increased risk of colorectal adenoma (OR, 1.29; 95% CI: (39,41)
1.03–1.63)

Alcohol consumption was associated with an increased risk of NCP in young adults aged 30–39 years (OR,
1.25; 95% CI: 1.17–1.33)

Diabetes Diabetes mellitus was associated with an increased risk of NCP (OR, 2.80; 95% CI: 1.06–7.42) (39,40)
mellitus and
Metabolic syndrome was associated with an increased risk of NCP in young adults aged 30–39 years (OR,
metabolic
1.33; 95% CI: 1.21–1.46). Elevated blood pressure (OR, 1.25; 95% CI: 1.16–1.35) and elevated triglyceride
syndrome
levels (OR, 1.24; 95% CI: 1.16–1.33) were also associated with an increased risk of NCP

Inflammatory Underlying inflammatory bowel disease was present in 15% (9/62) of patients ≤30 years old with CRC (43)
bowel disease
CRC, colorectal cancer; AYA, adolescent and young adult; NCP, neoplastic colonic polyps; OR, odds ratio; CI, confidence interval; BMI,
body mass index.

Lynch syndrome, familial adenomatous polyposis the conditions (59). Pearlman et al. have analyzed the
(FAP) and other rare syndromes including MutYH- prevalence of germline mutations associated with cancer
associated polyposis, Peutz-Jeghers syndrome, juvenile susceptibility among 450 CRC patients younger than
polyposis, polymerase proofreading-associated polyposis 50 years, and they revealed that 16% of patients had genetic
and Cowden/PTEN hamartoma syndrome (Table 3), cancer susceptibility (60). Thus, genetic testing should be
other hereditary cases remain unexplained (57,58). considered for all AYAs with CRC (61), although only a few
Patients with these genetic backgrounds tend to develop AYA-CRC patients do not undergo such tests in real-world
CRC earlier. In most hereditary CRC syndromes, practice. Details of the two most common syndromes,
polyps precede the development of carcinoma, but Lynch syndrome and FAP, are reviewed in this section,
the exact route to carcinoma seems to differ among and comprehensive descriptions of other syndromes are

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
Journal of Gastrointestinal Oncology, Vol 14, No 4 August 2023 1861

Table 3 Hereditary syndromes associated with AYA-CRC

Lifetime risk of Average age at CRC
Syndrome Responsible genes Frequency Clinical characteristics
CRC diagnosis (years)

Lynch syndrome MLH1, MSH2, 2–5% of all CRC 50–80% 40–45 Right-sided, locally advanced
(hereditary nonpolyposis MSH6, PMS2, tumors
CRC) EPCAM
Microsatellite instability-high
phenotype

Commonly associated with

various extracolonic cancers

FAP APC on 1–2% of all CRC Almost 100% 39 >100 adenomatous polyposis
chromosome (1:10,000–20,000) with average onset before
5q21 20 years old

Polyposis also found in the

stomach and duodenum

MutYH-associated MutYH About 1% of all 35–53% 35–45 Broad clinical spectrum

polyposis CRC sometimes resembling
attenuated FAP

Peutz-Jeghers STK11 <1% of all CRC 39% by age 70 60 Commonly associated with
syndrome (1:25,000–300,000) years extracolonic cancer

Melanocytic macules on lips,

perioral, and buccal regions

Juvenile polyposis MADH4 (SMAD4/ <1% of all CRC 17–68% by 35–45 Hamartomatous
syndrome DPC4), BMPR1A age 60 years polyposis throughout the
gastrointestinal tract

Polymerase POLE, POLD1 <1% of all CRC Reported to be 35–40 Sometimes associated with
proofreading-associated 80% in a small endometrial, breast, and/or
polyposis study brain tumors

Good response to immune

checkpoint inhibitors

PTEN hamartoma tumor PTEN <1% of all CRC 9–16% 40s Lifetime risks for a variety
syndrome (Cowden of cancers such as breast,
syndrome) thyroid, kidney, and skin
cancer
AYA, adolescent and young adult; CRC, colorectal cancer; FAP, familial adenomatous polyposis.

available in the guidelines of the Japanese Society for genetic stability (63). In Lynch syndrome, mismatch repair
Cancer of the Colon and Rectum (58). deficiency (dMMR) accelerates mutation accumulation
and increases the risk of carcinogenesis. dMMR-associated
cancer usually shows high tumor mutation burden and
Lynch syndrome
MSI-high phenotype (63). EPCAM is located upstream
Lynch syndrome is the most common hereditary syndrome of MSH2, and mutations in EPCAM can be another cause
associated with CRC. It is caused by germline mutations of Lynch syndrome. Hypermethylation of MLH1 can
in mismatch repair genes, such as MLH1, MSH2, MSH6, cause sporadic dMMR/MSI-high CRC, but this condition
and PMS2, and is inherited in an autosomal dominant is not considered Lynch syndrome. In individuals with
manner (62). These mismatch repair proteins correct Lynch syndrome, the lifetime risk of CRC development is
DNA replication errors and they are essential to maintain estimated to be 50–80%, and CRC is diagnosed between 40

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
1862 Ueno et al. CRC in AYA

and 45 years of age on average (37). Two teenage siblings of CRC approaches 100% in the absence of prophylactic
with multiple adenomas and CRC have been reported colectomy. The median age for the development of CRC
who had heterozygous variants in PMS2 and POLD1 (57). is 35–40 years in these patients (58). Approximately 80%
POLD1 mutations are also known as a cause of hereditary of all causes of death in FAP patients was CRC until the
CRC (64); thus, the coexistence of these variants may 1980s; however, the proportion has been decreasing to
have accelerated cancer predisposition. The Amsterdam approximately 60% since the 1990s. Among extracolonic
criteria have been used to identify those at risk of Lynch manifestations, desmoid tumors and duodenal cancer are the
syndrome; however, the sensitivity of these criteria is only leading causes of death, with incidences of approximately
78%; thus, Lynch syndrome should be suspected in young 10% and 6%, respectively (75). Patients with FAP should
patients with CRC and CRC patients with a history of undergo surveillance with sigmoidoscopy or colonoscopy
other cancers, even if they do not meet the Amsterdam every 1–2 years beginning at 10–11 years of age (73). Owing
criteria (65). The Amsterdam criteria has been revised in to a large number of polyps and the high risk of CRC,
1999 (66); however, its mutation detection rate was not patients with classic FAP should undergo prophylactic
improved enough compared to the original criteria (67). surgery in their 20s (37,58).
Mutations in BRAF are found in up to 12% of metastatic
CRC and BRAF V600E mutations are associated with Special consideration in the treatment of AYA-CRC
the female sex, right-sided and advanced CRC, and high
mutation burden (68), but these mutations are rare in Chemotherapy regimens
patients with Lynch syndrome; thus, BRAF-specific It is essential to test for MSI status before administering
immunohistochemistry may be useful to exclude Lynch chemotherapy to patients with AYA-CRC because they
syndrome (69). Some patients with clinical suspicion of are more likely to have MSI-high tumors, as mentioned
Lynch syndrome and MSI-high tumors lack pathogenic in the previous section; MSI-high CRC requires different
mutations in the mismatch repair gene; these patients are treatment strategies from microsatellite stable tumors.
defined as having mutation-negative Lynch syndrome or However, it remains unknown whether the optimal
Lynch-like syndrome (58). Lynch syndrome-related CRC treatment for AYA-CRC differs from that for CRC in
tends to be mucinous, high-grade, and right-sided (70). elderly patients. Kneuertz et al. reported that young patients
More than 80% of CRC cases in patients with Lynch (aged <50 years) with CRC received significantly more
syndrome demonstrate an MSI-high phenotype (45). postoperative chemotherapy but gained only a minimal
Other cancers associated with Lynch syndrome include gain in survival (76). These findings cannot be simply
endometrial, gastric, small bowel, hepatobiliary, urinary interpreted because MSI status was not assessed in this
tract, ovarian, and brain tumors. When a brain tumor arises study, but we should be aware that more intensive treatment
in patients with either Lynch syndrome or FAP, they are may not always be beneficial. In addition, while young
considered to have Turcot syndrome (71). Individuals with patients are less likely to develop severe neutropenia than
confirmed or suspected Lynch syndrome should undergo their older counterparts, the frequency of nausea is higher
colonoscopy for CRC screening every 1–2 years, beginning in young patients (77). For metastatic diseases, no age-
at the age of 20–25 years, which has been shown to reduce related differences in the efficacy of chemotherapy have
mortality risk (72,73). Surveillance of other cancers, been reported (78). Nonetheless, all previous studies were
including uterine, ovarian, gastric, and urinary tract cancers, limited by their study design or sample size; therefore,
should also be considered (73,74). further research with an adequate number of patients with
AYA, ideally randomized controlled trials, will be required
to clarify the optimal treatment for AYA-CRC.
FAP

FAP is the second most common hereditary syndrome

Fertility preservation
associated with AYA-CRC, occurring in 1/17,400
individuals (58). FAP is caused by a loss-of-function Fertility is a significant concern for AYAs diagnosed with
mutation in the APC gene. Hundreds to thousands of cancer. The total fertility rate has been reported to be lower
polyps arise throughout the large bowel and the lifetime risk in female CRC survivors than in the general population (79).

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
Journal of Gastrointestinal Oncology, Vol 14, No 4 August 2023 1863

Adhesions after pelvic surgery, radiotherapy, and systemic is needed for AYA-CRC survivors who have completed
chemotherapy can cause infertility. Chemoradiotherapy active anticancer treatment (87). Previous studies have
for rectal cancer is associated with a high risk of infertility shown that AYA-CRC survivors (≥2 years after diagnosis)
in female patients, whereas most standard chemotherapy have a 2.83-fold (95% confidence interval: 2.23–3.59)
regimens are associated with an intermediate-to-low higher risk of hospitalization than their siblings or matched
risk (80). The risk of chemotherapy-induced infertility general population (88). Because approximately 20% of
seems to differ according to the chemotherapy regimen; patients with AYA-CRC develop a secondary primary
5-fluorouracil (5-FU) is believed to cause a temporary neoplasm within 35 years, surveillance for a second primary
reduction in sperm count in men but has a low risk of malignancy may be required and the second cancer tends
causing amenorrhea in female patients, whereas oxaliplatin to be diagnosed within five years after the primary cancer
has been suggested to have moderate gonadal toxicity (81). diagnosis (89-91). CRC is the second most common
Various fertility preservation options can be offered to cancer after AYA-CRC, followed by cervical and thyroid
AYA patients with cancer. The Japan Society of Clinical cancers (89). On the other hand, stomach, liver and bile,
Oncology has published clinical practice guidelines for and pancreas cancers were reported to be leading causes
fertility preservation that recommend embryo (fertilized of secondary cancer-related deaths (92). In addition, it
oocyte) cryopreservation for female patients with a male has been reported that the health-related quality of life of
partner (grade B), unfertilized oocyte cryopreservation for AYAs with CRC is low, even in nonmetastatic patients (93).
female patients without a partner (grade C1), ovarian tissue Returning to work is sometimes challenging for CRC
cryopreservation for female patients who require urgent survivors (94,95), and a large questionnaire-based study
cancer-directed therapy or in whom ovulation induction revealed that 25% of young cancer survivors were
is difficult for oocyte harvesting (grade C1), and sperm unemployed (96). Psychosocial support and networking
cryopreservation for male patients (grade B) (82). Because through AYA patient communities will play an important
up to 88% of male patients experience sexual dysfunction role because these patients may have limited life experiences
after surgery for rectal cancer (83), nerve-sparing surgery is and underdeveloped coping skills (97). Especially, male
recommended when there is a risk of erectile or ejaculatory patients aged <50 years were reported to have a higher
dysfunction (82). The role of fertility preservation should risk of mental health disorders after diagnosis of CRC
be informed to patients before surgery, pelvic radiation, compared to average-age CRC patients (98). Several studies
and/or chemotherapy (74). However, in a case series on survivorship models for patients with AYA-CRC have
from the United States, only 20% of young women (aged been reported; however, evidence of their effectiveness is
18–45 years) with CRC received fertility counseling (84). In lacking (99). Moreover, most phase III therapeutic trials
a recent international cross-sectional study, approximately of AYAs in cancer have not included patient-reported
half of the young patients with CRC (aged <50 years) outcomes (100). Future studies focusing on the quality of
discussed reproductive health with their healthcare life of AYA-CRC survivors are warranted.
providers (85). In Japan, fertility preservation is often
provided for patients with breast or hematologic cancer,
Future perspectives for early diagnosis of
but rarely for patients with CRC (86). Physicians who treat
AYA-CRC
AYA-CRC patients should also explain fertility preservation
to patients before treatment. Educational strategies are needed to increase the awareness
of patients, primary care physicians, and gastroenterologists
to reduce the delayed diagnosis of AYA-CRC. First, AYAs
Survivorship
should be informed that they can develop CRC and that
Owing to the increased incidence and improved mortality the initial symptoms may be rectal bleeding, weight loss,
of AYA-CRC, the number of young CRC survivors is likely changes in bowel habits, abdominal pain, and/or iron
to increase in the coming decades. Survivors are at risk of deficiency anemia (74,101,102). Second, all physicians
CRC recurrence, second primary cancers, and the long- should consider screening for CRC in all AYAs complaining
term adverse effects of CRC and anticancer treatment of the above symptoms, especially if they have a family
and may suffer from psychological, reproductive, genetic, history of CRC (74). Finally, early detection of CRC in
social, and employment concerns. Thus, special attention asymptomatic AYAs remains a challenging issue because

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98
1864 Ueno et al. CRC in AYA

population-based CRC surveillance for AYAs has not been Peer Review File: Available at https://jgo.amegroups.com/
justified in terms of cost-effectiveness. However, every article/view/10.21037/jgo-23-98/prf
AYA in Japan can undergo individual opportunistic cancer
screening with out-of-pocket payment. Increased AYA- Conflicts of Interest: All the authors have completed the
CRC awareness may encourage AYAs to engage in out- ICMJE uniform disclosure form (available at https://jgo.
of-pocket CRC surveillance, as reported for breast cancer amegroups.com/article/view/10.21037/jgo-23-98/coif). The
screening (103). Kwak et al. prospectively evaluated the authors have no conflicts of interest to declare.
prevalence and characteristics of colorectal adenomas
in 4,286 asymptomatic young adults (aged 20–39 years) Ethical Statement: The authors are accountable for all
and found that 0.9% of the participants had advanced aspects of the work and ensure that questions related
adenomas (41). In particular, individuals aged >30 years, to the accuracy or integrity of any part of the work are
current smokers, and alcohol drinkers had a significantly appropriately investigated and resolved.
higher risk of developing adenomas. In a recent cross-
sectional study, the prevalence of colorectal neoplasia Open Access Statement: This is an Open Access article
in AYAs who underwent colonoscopic screening was distributed in accordance with the Creative Commons
14.9% (104). This information will help AYAs decide Attribution-NonCommercial-NoDerivs 4.0 International
whether to perform out-of-pocket CRC surveillance to License (CC BY-NC-ND 4.0), which permits the non-
avoid AYA-CRC-related deaths. We found that only a commercial replication and distribution of the article with
few studies have been reported from Japan; thus, further the strict proviso that no changes or edits are made and the
research is warranted. original work is properly cited (including links to both the
formal publication through the relevant DOI and the license).
See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
Conclusions

The incidence of AYA-CRC has increased in Japan and

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Cite this article as: Ueno A, Yokota M, Ueno M, Kawamoto

K. Colorectal cancer in adolescent and young adults:
epidemiology in Japan and narrative review. J Gastrointest
Oncol 2023;14(4):1856-1868. doi: 10.21037/jgo-23-98

© Journal of Gastrointestinal Oncology. All rights reserved. J Gastrointest Oncol 2023;14(4):1856-1868 | https://dx.doi.org/10.21037/jgo-23-98