Rectal Cancer in Young Adults: A Single Center Experience

Abstract

Purpose:

Individuals below the age of 40 make up only 3%–11% of colorectal cancer (CRC) cases. In this study, we aimed to review clinicopathological characteristics of rectal cancer in young adults.

Methods:

Rectal adenocancer patients aged ≤40 were included in this study from Antalya Training and Research Hospital. A single-arm descriptive study was designed.

Results:

There were 85 patients in the final analyses (n = 85). The median age was 37 (19–40). Mucinous adenocarcinoma and signet-cell carcinoma rates were 11.8% for each. Twenty patients (24.4%) had high-grade cancer. Fourteen patients (16.5%) had CRC history in a first-degree relative. None of the patients were diagnosed through a screening test. Of the 85 patients, 41 (48.2%) were stage 3 and 23 (27.1%) were stage 4 at the time of diagnosis. Thirty-four (54.8%) of the 62 nonmetastatic patients had neoadjuvant and 27 (43.5%) had adjuvant treatment because of having an upfront surgery before presentation. In the nonmetastatic population, the 5-year disease-free survival rate was 69.7 ± 6.5%. De-novo metastatic underwent chemotherapy, and biological agents were administered when feasible. KRAS mutation rate was 56.5% among metastatic patients. The median progression-free survival for the first-line treatment was 11.2 months (5.7–16.6), and the median overall survival was 22.3 months (15.4–29.1).

Conclusion:

We demonstrated that rectal cancer is usually diagnosed at late stages in young individuals which is compatible with the previous reports. Low cancer awareness in young patients and their caregivers and adverse histological features were advocated as the reason for the diagnostic delay. However, future studies may elucidate the reason behind the common diagnosis at advanced stages.

Introduction

Colorectal cancer (CRC) is the most common gastrointestinal cancer. It accounts for the third most common cancer and second most common cause of cancer-related mortality worldwide.¹ The risk of CRC is associated with age. In total, 10%–12% of all CRC cases occur in the population aged <50, while only 3% are aged below 40 years.² However, in both the United States and Europe, CRC incidence before the age of 50 has been increasing.^3,4 Surveillance Epidemiology End Results (SEER) data of the United States from 1998 to 2019 reveal a continuous increase in CRC incidence for the population aged between 20 and 49. Since 2003, the incidence rate of CRC has risen by 2% per year in young adults.⁵ This pattern of incidence led to a recommendation change about screening beginning age in the standard risk population, from 50 to 45, by the United States Preventive Services Task Force. This strategy is estimated to prevent 4% of CRC cases annually.⁶ Unfortunately, the younger proportion of CRC cases is estimated to rise in the future, despite the earlier screening recommendation.⁷ This increasing trend in early-onset colorectal cancer (EOCRC) is more relevant to regional and advanced disease rather than localized cancer.^1,2 Likewise, the mortality rates in older adults continue to decline, while it is stagnant at 2.8 per 100.000 in young.⁸

Despite the lack of comprehensive SEER data on CRC in Turkey, the findings revealed that 11.0% of rectum cancer cases and 8.0% of colon cancer cases occurred in individuals under 40 years old, indicating a serious health problem in the young population.⁹ The clinical guides in Turkey recommend screening with colonoscopy or occult blood test-based stool tests after age 50 at standard risk population.¹⁰

EOCRC tends to occur in distal parts of the large bowel and rectum.¹¹ Furthermore, young age is related to a different behavior than it is in older patients. EOCRC exhibits characteristics such as delayed diagnosis, diagnosis at more advanced stages, and a higher prevalence of aggressive histology (such as signet-ring cell histology and high-grade cancers). As a result, EOCRC is associated with a less favorable prognosis.^12,13 In total, 16%–35% of the EOCRC occur in individuals affected by a hereditary cancer syndrome, and most of those are associated with Lynch syndrome. Eventually, most of the EOCRC cases are sporadic.¹⁴ Despite these data, the underlying mechanism of the different disease characteristics varying by age is still unclear.

To better understand the unique features of the disease in the young population, we aimed to review the young onset rectum cancer patients. We evaluated the clinical, genetic, and pathological features, treatment modalities and survival outcomes of rectum cancer patients in the population aged ≤40 whose risk increase is prominent at a single center and interpreted the descriptive data with literature.

Material-Method

Study population

We screened the patients who were diagnosed with rectal adenocarcinoma and presented to the medical oncology department of Antalya Training and Research Hospital from January 2010 to September 2023. Patient follow-up file archive and electronic archive were accessed and 108 files were extracted. Exclusion criteria were having a mesenchymal and/or neuroendocrine histology, being younger than 18 or older than 40 years, and being lost to follow-up. We conducted this study in accordance with the Declaration of Helsinki and with approval from the Ethics Committee (No. 2024-022).

Management policy and data collection

All the patients who were diagnosed with rectal cancer were managed with the best practice feasible and recommended at the date. Age, sex, body mass index, smoking history, family history, diagnostic procedure, primary complaint at presentation, primary tumor location from the anal verge (0–5 cm as distal rectum; 5–10 cm as mid-rectum; 10–15 cm as proximal rectum), tumor-node-metastasis stage, pathological type, genomic alterations, and dates of death (if occurred) were recorded for all the patients. RAS and RAF analyses were performed via polymerase chain reaction testing and microsatellite instability was tested by immunohistochemistry for mismatch repair proteins. For nonmetastatic patients, neoadjuvant or adjuvant treatment data, surgery details, surgical pathology records, and recurrence details (if occurred) were recorded. For de-novo metastatic patients, systemic treatment types, local treatment data, and treatment responses were collected.

Family history was considered positive if there was at least one histologically proven CRC case in the first-degree relatives of the patients. American Joint Cancer Committee Staging system was applied for all the patients as T, N, and M in this study, either clinically or pathologically. The histological type of tumor was specified if it was mucinous adenocarcinoma or signet-ring cell carcinoma. Surgery procedures were abdominoperineal resection or sphincter sparing surgery, which comprises low anterior resection, ultralow anterior resection, and inter-sphincteric resection. Long course radiotherapy (LCRT) was a total 50.4 Gy dose in 25–28 fractions with the administration of concurrent 5-fluoropyrimidine-based chemotherapy. However, short-course radiotherapy (SCRT) was 25 Gy total radiation dose in five fractions without concurrent chemotherapy.

The data generated in this study are available upon request from the corresponding author.

Statistical analysis

The statistical analyses were performed via IBM SPSS Statistics version 26.0. Continuous variables were given as mean ± standard deviation. Otherwise, the median value was used with the min-max values in the brackets. Survival data were displayed by the Kaplan–Meier method. For the patients who were diagnosed at an early or locoregional stage, disease-free survival (DFS) was calculated from the operation date to the latest control or recurrence date. For those patients who had metastatic spread at the time of diagnosis and were not treated with curative intent, progression-free survival (PFS) was calculated from the initiation of the treatment date to the disease progression date or the date of death or the latest control date. The overall survival (OS) duration was calculated from the initiation of treatment to the latest control date or the date of death. Survival analysis was not conducted for subgroups with fewer than 20 patients due to the small sample size.

Results

Patient characteristics

A total of 108 patients were screened retrospectively (n = 108). Twenty-three of those were not meeting the inclusion criteria. Eighty-five patients were available for statistical analyses (n = 85). Median follow-up time was 31.4 (2.2–179.5) months. The median age of the study population was 37 years (19–40). There were 41 women (48.2%) and 44 men (51.8%). Eastern Cooperative Oncology Group performance status was 0 or 1 in the vast majority of the patients. Fourteen (16.5%) patients had one or more CRC cases in their first-degree relatives. Thirty-three patients (38.8%) had a smoking history. None of the patients were diagnosed via a screening program. The percentage of mucinous and signet cell carcinoma was 11.8% for each. Forty-one (48.2%) were stage 3 and 23 (27.1%) were stage 4 at the time of diagnosis (Table 1).

Table 1.

Clinical and Pathological Characteristics of the Entire Cohort

	N	%
Sex
Female	41	48.2
Male	44	51.8
ECOG Performance Status
0	25	29.4
1	52	61.2
2	8	9.4
Smoking History
Positive	52	61.2
Negative	33	38.8
CRC Family History
Positive	14	16.5
Negative	71	83.5
BMI (kg/m²)
≥30	11	12.9
<30	14	87.1
Diagnosis through Any Screening Program	0	0
Complaint at Diagnosis
Rectal Bleeding	36	42.4
Abdominal Pain	20	23.5
Obstruction/Constipation	20	23.5
Tenesm	5	5.9
Weight Loss	4	4.7
Tumor Localization in Rectum
Distal (0–5 cm)	19	22.4
Middle (5–10 cm)	32	37.6
Proximal (10–15)	34	40.0
Histology
Mucinous Adenocarcinoma	10	11.8
Signet Ring Cell Carcinoma	10	11.8
Nonspecific (Adenocarcinoma)	65	76.4
Histological Grade
1	7	8.2
2	55	64.7
3	20	23.5
Unknown	3	3.5
T stage
1	0	0
2	9	10.6
3	58	68.2
4	18	21.2
N stage
Negative	21	24.7
Positive	64	75.3
TNM Stage
I	1	1.1
II	20	23.5
III	41	48.2
IV	23	27.1
MSI
MSI-High	5	5.9
MSI-Low/Stable	62	72.9
Unknown	18	21.1

BMI, body mass index; CRC, colorectal cancer; ECOG, Eastern Cooperative Oncology Group; MSI, microsatellite ınstability; TNM, tumor-node-metastasis.

Treatment data of the patients

Twenty-three patients were stage 4 at diagnosis. These patients received chemotherapy and biological agents if feasible. Thirteen (56.5%) had KRAS mutation, 1 (4.3%) had BRAF mutation and NRAS was wild type in all de-novo metastatic patients. Two patients (8.6%) presented after an upfront surgery because of a local tumoral complication. Four (17.2%) patients had undergone preplanned primary tumoral surgery after a near-complete response to chemotherapy. Two of those patients had SCRT before the operation. After the first-line systemic treatment, 19 patients (82.6%) experienced disease progression. Eleven (57.8%) of those 19 patients could receive a subsequent-line systemic antineoplastic treatment (Table 2).

Table 2.

Clinical and Treatment Data of De-Novo Metastatic Patients

	n	%
Age Group (years)
≤35	9	39.1
36–40	14	60.9
Metastasis Sites
Liver	13	56.5
Non-Regional Lymph Nodes	12	52.1
Lung	9	39.1
Periton	8	34.7
Ovary	4	17.3
Bone	3	13.0
Genomic Mutation Profile
KRAS Mutant/Wild/Unknown	13/10/0	56.5/43.5/0
NRAS Mutant/Wild/Unknown	0/21/2	0/91.3/8.7
BRAF Mutant/Wild/Unknown	1/20/2	4.3/87.0/8.7
MSI Status
MSI-High	0	0
MSI Low-Stable	16	69.6
Unknown	7	30.4
First-Line Chemotherapy
Doublet Chemotherapy + Anti VEGF	10	43.4
Doublet Chemotherapy + Anti EGFR	8	34.8
Triplet Chemotherapy + Anti VEGF	1	4.3
Triplet Chemotherapy + Anti EGFR	0	0
Doublet Chemotherapy Only	4	17.4
Surgical Treatment Data
Urgent Palliative Surgery	2	8.7
Preplanned Surgery for Primary Tumor	4	17.4
Curative Metastasectomy	5	21.7
Second-Line Systemic Therapy After Progression on First Line (n = 19)^a
Yes	11	57.8
No	8	42.2

19 patients progressed after the first line therapy.

EGFR, epithelial growth factor receptor; MSI, microsatellite ınstability; VEGF, vasculoendothelial growth factor.

Of the 62 nonmetastatic patients, 9 (14.5%) received total neoadjuvant therapy, 25 (40.3%) received perioperative treatment, and 27 (43.5%) received all the planned therapy in the adjuvant setting since they were presented after an upfront surgery. One patient did not receive any antineoplastic therapy except for a curative surgery, as a consequence of the patient’s own decision. 9 (26.4%) patients in the neoadjuvant subgroup (n = 34) had total neoadjuvant treatment (TNT) while the other 25 (73.7%) had perioperative chemotherapy in sequence with neoadjuvant LCRT. Of the neoadjuvant therapy subgroup, 3 patients did not undergo surgical treatment. One patient was being closely observed by watch and wait method after receiving TNT, one patient was still having neoadjuvant therapy at the time of data collection and one patient had disease progression under neoadjuvant treatment (Table 3). In the neoadjuvant therapy subgroup, all the patients received LCCRT and the median duration between the completion of radiotherapy to surgery was 10.0 weeks (2.0–26.0). In the adjuvant therapy subgroup, 3 (11.1%) patients could not receive the planned adjuvant radiation therapy (one had contraindication (prior local radiation history), and two had disease progression).

Table 3.

Clinical and Treatment Data of Nonmetastatic Patients

	n	%
Age group (years)
≤35	21	33.9
36–40	41	66.1
Obstruction at Diagnosis
Yes	11	17.7
No	51	82.3
Treatment Type
Total Neoadjuvant Therapy	9	14.5
Perioperative Therapy	25	40.3
Adjuvant Therapy (Upfront Surgery)	27	43.5
Only Surgery^a	1	1.6
Genomic Mutation Profile
MSI-High	5	8.1
MSI Low-Stable	45	72.6
Unknown	12	19.4
Surgery Type
Sphincter Sparing Surgery	49	79.0
APR	10	16.1
No Surgery^b	3	4.8

1 patient preferred not to receive either neoadjuvant or adjuvant treatment.

1 patient was under watch and wait after total neoadjuvant treatment, 1 patient was still having neoadjuvant therapy at the time of data collection and 1 patient had disease progression under neoadjuvant treatment.

APR, abdominoperineal resection; MSI, microsatellite ınstability.

Survival outcomes

The median DFS time was not reached for the nonmetastatic patients (n = 62). Eighteen patients (29.0%) experienced any recurrence events at the time of data collection. The 2-year DFS rate was 78.8 ± 5.5% and the 5-year DFS rate was 69.7 ± 6.5% (Fig. 1). All the recurrence events occurred as distant metastasis, and the most affected organs were the liver (38.9%), lung (38.9%), lymph nodes (38.9%), peritonitis carcinomatosa (27.8%) and bone metastasis (5.0%). Moreover, local recurrence was also observed in addition to distant metastasis in 4 patients (22.2%). The nonmetastatic group did not reach (NR) the median OS, as 16 patients (25.8%) died. The 5-year OS rate was 75.2 ± 6.1%, and the 8-year OS rate was 66.8 ± 7.8% (Fig. 1).

FIG. 1.

(A) Disease-free survival graphic of nonmetastatic patients at the time of diagnosis.(B) Overall survival graphic of nonmetastatic patients at the time of diagnosis.

The median PFS for the first-line treatment (PFS-1) was 11.2 months (5.7–16.6) for de-novo metastatic patients (n = 23). The 24-month PFS-1 rate was 22.5 ± 10.0%. Nineteen (82.6%) of those patients had progressed after the first-line treatment. However, only 11 patients received a second-line treatment. Due to the low number of patients receiving second-line systemic therapy, the calculation for PFS-2 was not performed. The median OS of de-novo metastatic patients was 22.3 months (15.4–29.1). The 3-year OS rate was 22.1 ± 10.0% (Fig. 2).

FIG. 2.

(A) Progression-free survival graphic for the first-line treatment of de-novo metastatic patients. (B) Overall survival graphic of de-novo metastatic patients.

Further survival analysis was performed after dividing the groups according to age with a cut-off point of 35 years. In the metastatic patients group, 9 (39.1%) were aged ≤35 years and 14 (60.9%) were between 36 and 40 years (Table 2). The patient numbers in these subgroups were insufficient to conduct a robust survival analysis.

In the nonmetastatic group, 21 (33.9%) were ≤35 and 41 (66.1%) were between 36 and 40 years (Table 3). The median DFS were similar for those aged ≤35 and aged 36–40 [95% Confidence interval (CI); 7.9 years (2.7–13.0) and 8.2 years (NR-NR), respectively, (log-rank, p = 0.372)] (Fig. 3A). The median OS was not reached for those aged ≤35. Five-year OS rates for those aged ≤35 and aged 36–40 were 70.4 ± 10.2% and 77.9 ± 7.5%, respectively (log-rank, p = 0.913) (Fig. 3B).

FIG. 3.

(A) Median disease-free survival was similar between those aged ≤35 and aged 36–40 [95% Confidence interval (CI); 7.9 years (2.7–13.0) and 8.2 years (NR-NR), respectively (log-rank, p = 0.372)]. (B) Five-year OS rates for those aged ≤35 and aged 36–40 were 70.4 ± 10.2% and 77.9 ± 7.5%, respectively (log-rank, p = 0.913).

Discussion

In this study, we have demonstrated that rectum cancer was diagnosed at stage 3 and stage 4 in 75.3% of young adults. Only 54.8% of the nonmetastatic patients could receive neoadjuvant treatment. KRAS gene mutation was present in 56.5% of de-novo metastatic patients. Moreover, 42.2% of the 19 patients who had disease progression after the first-line treatment could not receive any second-line systemic therapy.

There is an important increment in the incidence of CRC in young individuals. This rising trend is more relevant to rectum cancer than it is to colon cancer. It is estimated that by 2030 one of all ten colon cancers and one of all four rectal cancers will be diagnosed before the age of 50.¹⁵ This situation changed the age for screening beginning at the standard risk population, from 50 to 45.² The second major point to begin screening is family history after the age. In total, 16.5% of the patients in our study had a positive family history but were not diagnosed by a screening program. The other 83.5% would never be screened for CRC by the indication of age unless they would present with their complaints. All the patients in our cohort had symptoms leading to the cancer diagnosis. On the other hand, inflammatory bowel disease increases CRC and indicates early-age screening. However, none of our patients were under routine follow-up for a chronic bowel disease.

75.3% of our patients were diagnosed at stage 3 or stage 4. Similarly, Yeo et al.¹⁶ found that 72.6% of their young CRC patients under 40 years were diagnosed at stages 3 and 4. A report by Emile et al.¹⁷ demonstrated that the ratio of stages 3 and 4 at diagnosis was 56.8% in patients below 40. However, it was 41.7% in another report representing an age-unselected European cohort composed of 849 patients.¹⁸ Moreover, in 2021, the Turkish Cancer Control Programme Report declared that advanced-stage diagnosis is 24.1% regardless of age. These data suggest that the proportion of stage 3 and 4 diagnosis is similar with the data highlighted for the same age group in literature. In previous studies, it was claimed that cancer suspicion is low in both young patients and their caregivers, which causes a diagnostic delay of about two years compared to older adults.^12,19–21 Despite our study not providing information about the duration from symptoms to the first doctor visit, the average time from the beginning of symptoms to presentation was found to be 6 months in young adults.²² The high proportion of diagnoses at advanced stages in our cohort may be because of being a referral center. On the other hand, the coverage of CRC screening was reported as 30%–40% in our country and 70% was aimed to achieve positive results.¹⁰

Focusing on the nonmetastatic patients, only 54.8% could receive neoadjuvant treatment. The rest were presented to medical oncology after having an upfront surgery. Reasonably, 17.7% had obstruction at the time of diagnosis could have led to upfront surgery. On the other hand, the proximal rectum was the primary tumor localization in 40% of the whole cohort, which might also have led to skipping the neoadjuvant treatment.

In the context of the prognosis of rectal cancer in young adults, there are conflicting results in the literature. While some reports emphasize a worse prognosis in young,^19,23 the others do not.^16,24 Nevertheless, the age cut-off was 50 years in most of those studies and most of them did report whole CRCs rather than rectum cancer alone, which may not represent the real-life data since the change of screening recommendation age from 50 to 45. We demonstrated that the 5-year DFS rate was 69.7 ± 6.5% in our nonmetastatic patients. Emile et al. showed that 3 years of DFS was 74.2% and 75% in patients aged ≤40 and >40, respectively (p = 0.90). Looking at the metastatic patients, we showed that only 57.8% received second-line therapy. Even though the retrospective data were insufficient to put a solid reason for this low ratio of second-line treatment, being able to receive only one line of therapy can be considered an indicator of poor prognosis. The median PFS-1 was 11.2 months (5.7–16.6) and the median OS was 22.3 months (15.4–29.1). In a comparative review which reported the data of 2426 CRC cases, of which 3% were under 40, no survival difference was found by age.¹⁶ In that study, it was reported that mucinous and signet ring cell histology rates were 11% and 9.6%, respectively, in the population below 40 years and the grade 2 tumor rate was 72.9%.¹⁶ These results were quite similar to the histological features of our cohort, since it may have a significant effect on prognosis.

The limitations of this study were being performed in a single-center and lacking a control group of older patients. The nature of retrospective design may be associated with patient selection bias. There was missing genomic data due to old records, similar to the previous retrospective studies.¹⁷ On the other hand, the assets of our data restricted attention to rectal cancer only as a specified tumor localization in a very young population. Since one-third of CRCs are located in the rectum and only 3% of all CRC patients are aged below 40, our 85-patient cohort represents a large amount of CRC patient population. Moreover, rectal cancer is distinct from colon cancer in terms of treatment strategies and prognosis,²⁵ which makes our data valuable.

Conclusion

In this study, we have demonstrated that young adults with rectal cancer are usually diagnosed at advanced stages. The reason was associated with low levels of cancer awareness,^19,20 and/or the aggressive biology of the disease^19,23,26 in the literature. However, elucidating the main reason should be the subject of future studies. The survival data is promising for the nonmetastatic stages in our cohort, which underlines the importance of early tumor detection. However, the main limitation of our study was that it lacked an older control group since it was designed as a single-arm study. The local permissions and approvals were taken per this designation. Future studies may compare these young patients with their older counterparts to highlight the differences and especially the survival data. Considering the increasing incidence rates of CRC in young individuals, as clinicians, we must be aware of the risk factors, screening programs, clinical symptoms, and potentially long survival when diagnosed early.

Footnotes

Authors’ Contributions

H.G.G.: Interpretation of the data, drafting and writing the article; M.K.: Interpretation of the data, review of the article and critical corrections; M.Y.: Interpretation of the data; B.Ö.: Interpretation of the data, data analysis; D.K.S.: Interpretation of the data; M.K.: Interpretation of the data.

Author Disclosure Statement

The authors declare no potential conflict of interest

Funding Information

No funding was received for this article.

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