Effect of family history on detection of adenomas and sessile serrated lesions in individuals aged 40s

Abstract

BACKGROUND

According to the guidelines in the United States, individuals with a family history of colorectal cancer should be screened at the age of 40 years. Data on the prevalence of adenomas and sessile serrated lesions (SSLs) in individuals aged 40-49 years in Japan are lacking.

AIM

To investigate the effect of family history on the detection of adenomas and SSLs during colonoscopy in Japan.

METHODS

This retrospective, single-center cohort study included individuals aged 40-79 years who underwent colonoscopy by expert endoscopists with an adenoma detection rate (ADR) ≥ 40% between 2021 and 2024. The ADR and adenoma plus SSL detection rate (ASDR) were investigated according to age. Multivariable analyses were performed to examine the effects of first-degree family history of colorectal cancer, fecal immunochemical test, and sex on the ADR and ASDR for each age group. A binomial logistic regression model was used.

RESULTS

In 10248 participants, the overall ADR and ASDR were 53.6% and 59.1%, respectively. The ADR and ASDR increased with age. Among 2317 participants aged 40-49 years, the presence of a family history significantly increased the ADR (47.6% vs 38.2%). The odds ratio of a family history for the ADR adjusted by sex and fecal immunochemical test was 1.59 (95% confidence interval: 1.13-2.25). In contrast, there was no significant association between the ADR and family history in participants aged 50-59, 60-69, and 70-79 years. Similarly, a family history significantly increased the ASDR (58.0% vs 43.7%) in participants aged 40-49 years. The odds ratio of a family history for the ASDR was 1.92 (95% confidence interval: 1.36-2.71).

CONCLUSION

Participants with a family history exhibited significantly elevated ADR (47.6%) and ASDR (58.0%), in their 40s. Individuals with a family history should initiate colonoscopy at 40 years old.

Key Words: Age; Family history; Colorectal neoplasia; Colonoscopy; Sessile serrated lesions

Core Tip: Participants in their 40s with a family history showed a high adenoma detection rate (47.6%) when expert endoscopists performed colonoscopies using the latest endoscopic system. There was a significant increase in the adenoma detection rate in those with a family history compared to those without, among participants aged 40-49 years.

INTRODUCTION

Colorectal cancer (CRC) is a fatal disease that occurs worldwide[1,2]. As CRCs mainly develop from conventional adenomas or sessile serrated lesions (SSLs), their removal prevents the development of CRC[3,4]. Colonoscopic screening can decrease the incidence and mortality of CRC[5]. First-degree relatives (FDRs) of patients with CRC have a three-to-six-fold increased risk of developing CRC, and therefore, early screening colonoscopy has been recommended for such individuals[6,7]. United States guidelines recommend that individuals with an FDR who had had CRC or a colorectal adenoma before the age of 60 years, or in two or more FDRs regardless of age, begin colonoscopic screening either at 40 years of age or at 10 years younger than the age of the index FDR[8]. Fuchs et al[9] reported the cumulative incidence of CRC among participants with and without a family history, and their data underpin average-risk screening programs and their recommendations to initiate screening at the age of 50 years. The cumulative incidence of CRC in participants with FDR history approaches the same threshold as those with no family history 10 years earlier, at age of 40 years[9]. Therefore, guidelines recommend early initiation of screening for individuals with a family history. However, little is known about the prevalence of colorectal neoplasia in individuals aged 40-49 years in Japan. Therefore, we analyzed the prevalence of colorectal neoplasia in young populations and the impact of FDR history.

MATERIALS AND METHODS

Study overview

This retrospective cohort study was conducted at the Toyoshima Endoscopy Clinic in Tokyo, Japan. Participants aged 40-79 years who underwent colonoscopy at our clinic between March 2021 and October 2024 were eligible for this study. Indications for colonoscopy included symptom evaluation, positive fecal immunochemical test (FIT) results, and screening and surveillance of colorectal polyps. Symptoms included hematochezia, abnormal bowel habits, and abdominal pain. Colonoscopy was performed by seven expert endoscopists with adenoma detection rates (ADRs) ≥ 40%. The ADR was inversely associated with the risks of interval CRC, advanced-stage interval CRC, and fatal interval CRC[10,11]. Hilsden et al[12] reported that endoscopists with an ADR of 39% or more had high accuracy. Patients with poor bowel preparation, incomplete cecal intubation, inflammatory bowel disease, or treatment purposes such as polypectomy or hemostasis were excluded. This study was approved by the Certified Institutional Review Board of the Yoyogi Mental Clinic on July 16, 2021 (Approval No. RKK227). We have published the study protocol on our clinic’s website (https://www.ichou.com/); thus, patients could opt out of the study if they desired. All the clinical investigations were conducted in accordance with the ethical guidelines of the Declaration of Helsinki.

Colonoscopy

The endoscopy system used was an Olympus EVIS X1 (CV-1500; Olympus Corp., Tokyo, Japan). The colonoscopy models used were CF-EZ1500D, CF-XZ1200, CF-HQ290, CF-HQ290Z, CF-H290EC, PCF-H290Z, and PCF-PQ260 (Olympus Corp, Tokyo, Japan). Sedation was performed at the patient’s discretion. Midazolam, pethidine, and/or propofol were used[13]. Pancolonic chromoendoscopy with indigo carmine was used routinely[14]. Moreover, endoscopic observation was performed using white-light imaging and/or texture and color enhancement imaging[15-17]. All polyps diagnosed as adenomas or SSLs were resected during the colonoscopy. The diagnosis of polyps was made histologically based on the resected specimens. Endoscopic resection techniques include endoscopic mucosal resection and hot or cold polypectomy using snares or forceps[18]. Index colonoscopy was defined as the first colonoscopy performed during the patient’s lifetime. Bowel preparations were classified into four groups: (1) Grade A was considered good; (2) Grade B was average; (3) Grade C was marginal; and (4) Grade D was poor[19]. Patients with grade D preparations were excluded from this study.

Data collection and outcome parameters

Our electronic endoscopy reporting system was the T-File system (STS Medic, Inc., Tokyo, Japan) integrated into the electronic medical record system Qualis (BML, Inc., Sapporo, Japan)[20]. The endoscopy reporting system outputted the information for this study in a Microsoft Excel (Microsoft, Redmond, WA, United States) file format. The background information included patient age, sex, colonoscopy indications, first-degree family history of CRC, endoscopist, endoscopy system, and bowel preparation. The outcome parameters were premalignant polyp detection rates such as the ADR and adenoma plus SSL detection rate (ASDR).

Statistical analysis

The ADR and ASDR were investigated according to age group. Age groups included 40-49 years, 50-59 years, 60-69 years, and 70-79 years. The Cochran-Armitage (CA) trend test was used to calculate the statistical significance of the ADR and ASDR trends across age groups. Multivariable analyses were performed to examine the effects of a first-degree family history of CRC on the ADR and ASDR for each age group. Odds ratios (ORs) were calculated using a binomial regression model and adjusted for the FIT results and sex. Statistical significance was set at P < 0.05. Calculations were performed using Bell Curve for Excel, version 4.09 (Social Survey Research Information Co., Ltd., Tokyo, Japan).

RESULTS

During the study period, 10753 consecutive patients aged 40-79 years who underwent colonoscopies performed by seven expert endoscopists were enrolled. Two patients with poor bowel preparation, 157 with inflammatory bowel disease, and 346 receiving treatments were excluded. Finally, 10248 participants were included in this study. The mean age was 57.1 years, and 44.8% were male (Table 1). The index colonoscopy rate showed a decreasing trend with age (P < 0.001, CA trend test). The overall ADR and ASDR were 53.6% and 59.1%, respectively. The ADR and ASDR by age and sex are shown in Figure 1, respectively. The ADR and ASDR showed an increasing trend with age (all P < 0.001). The ADR and ASDR were higher in men than in women in all age groups, except for the ASDR in those aged 70-79 years.

Figure 1 Adenoma detection rate and adenoma plus sessile serrated lesion detection rate by age and sex. A: Adenoma detection rate showed a significant increasing trend with age, and was significantly higher in men than in women in all age groups; B: Adenoma plus sessile serrated lesion detection rate showed a significant increasing trend with age, and was significantly higher in men than in women in participants aged 40-49 years, 50-59 years, and 60-69 years. ^aP < 0.01; ^bP < 0.001. ADR: Adenoma detection rate; ASDR: Adenoma plus sessile serrated lesion detection rate.

Table 1 Patient characteristics, n/%.

	All	40s	50s	60s	70s
Number	10248	2317	3564	2540	1827
Mean age (years)	57.1	45.2	54.6	64.0	74.0
Male sex	44.8	43.0	44.1	46.2	46.3
Family history	8.2	6.2	7.5	9.7	8.5
Positive FIT	13.2	18.9	14.1	10.3	10.1
Index colonoscopy	21.0	34.7	22.5	14.6	9.8
ADR	55.1	38.8	54.7	61.9	67.0
ASDR	59.0	44.5	58.5	65.2	69.7

FIT: Fecal immunochemical test; ADR: Adenoma detection rate; ASDR: Adenoma plus sessile serrated lesion detection rate.

The presence of a family history significantly increased the ADR (47.6% vs 38.2%) in patients aged 40-49 years. The OR of a family history of ADR adjusted by sex and FIT results was 1.59 [95% confidence interval (CI): 1.13-2.25, P = 0.008]. In contrast, there was no significant association between the ADR and family history in participants aged 50-59 years, 60-69 years, and 70-79 years (Table 2). Similarly, a family history significantly increased the ASDR (58.0% vs 43.7%) in patients aged 40-49 years. The OR of a family history for the ASDR adjusted by sex and FIT results was 1.92 (95%CI: 1.36-2.71, P < 0.001, Table 3).

Table 2 The effect of family history on adenoma detection rates based on age, %.

	Family history (-)	Family history (+)	Odds ratio	95%CI	P value1
40s	38.2	47.6	1.59	1.13-2.25	0.008
50s	54.9	52.4	0.96	0.74-1.23	0.73
60s	61.7	63.4	1.09	0.83-1.44	0.52
70s	66.6	70.1	1.19	0.85-1.66	0.31

¹P value was calculated using a binomial regression model and adjusted by sex and fecal immune test results.

CI: Confidence interval.

Table 3 The effect of family history on adenoma plus sessile serrated lesion detection rates based on age, %.

	Family history (-)	Family history (+)	Odds ratio	95%CI	P value1
40s	43.7	58.0	1.92	1.36-2.71	< 0.001
50s	58.5	58.7	1.06	0.83-1.37	0.63
60s	64.9	68.3	1.19	0.90-1.59	0.22
70s	69.6	70.1	1.03	0.74-1.44	0.84

¹P value was calculated using a binomial regression model and adjusted by sex and fecal immune test results.

CI: Confidence interval.

DISCUSSION

In this study, participants with a family history exhibited significantly elevated ADR (47.6%) and ASDR (58.0%) in their 40s. There were significant increases in ADR and ASDR in those with a family history compared to those without, particularly among those in their 40s. In Japan, annual FIT starting at 40 years of age has been adopted as a population-based CRC screening program[4]. Population-based colonoscopy screening is not recommended in Japan. Recently published guidelines by the American Gastroenterological Association suggest that individuals carrying mid-risk CRC probability should commence screening protocols at the age of 45 years, while those with exacerbated CRC risk owing to an FDR developing CRC should commence screening protocols at least 10 years prior to the age of CRC development within said relative or commence screening at the age of 40 years[21]. Our study supports the recommendation that patients with a family history should undergo screening colonoscopy at 40 years of age.

A recent meta-analysis showed that a family history of CRC in FDRs was associated with increased risk of adenoma (pooled OR = 1.67, 95%CI: 1.46-1.91)[22]. Furthermore, a sub-analysis by the number of FDRs was performed. Participants with two or more affected FDRs were at a particularly elevated risk (pooled OR = 4.18, 95%CI: 1.76-9.91), whereas patients with only one affected FDR were at a lower risk (pooled OR = 1.63, 95%CI: 1.35-1.96). The sub-analysis by age showed that family history was consistently associated with significant increases in ADRs in individuals aged over as well as under 50 years.

In contrast, our study showed a significant difference only in patients in their 40s with no significant differences observed in those in their 50s, 60s, or 70s. The rate of index colonoscopy decreased significantly with age (P < 0.001, CA trend test). When all the adenomas were removed during the index colonoscopy, they could not be detected during the second colonoscopy. Patients in their 50s, 60s, and 70s had low rates of index colonoscopy and may have previously undergone endoscopy and polypectomy. Differences in the index rates can cause bias, and the effect of family history may have been underestimated among participants in their 50s, 60s, and 70s.

When characterizing adenomas in young patients with a family history of CRC, the possible contribution of germline mutations should be considered. Representative genes include adenomatous polyposis coli, mutY DNA glycosylase, and genes involved in mismatch repair. These genes are respectively associated with familial adenomatous polyposis, mutY DNA glycosylase-associated polyposis, and Lynch syndrome[23]. New inherited CRC risk genes, including Axin 2, DNA polymerase epsilon, MutS homolog 3, and Nth like DNA glycosylase 1 have recently been identified[24]. Genetic predisposition could be an important direction for future studies. The strength of this study is that the endoscopists were limited to those with an ADR of 40% or more, and the latest endoscopic system, Olympus EVIS X1, was used. Colonoscopies were performed by experts using the newest system, providing highly accurate results and minimizing the risk of overlooking premalignant polyps. This study has some limitations. First, this was a retrospective, single-center study. However, the medical data recordings were well-controlled. Second, the patient cohorts were limited. Third, cost analysis was not performed. A detailed cost-effectiveness analysis is a topic for future research.

CONCLUSION

Participants with a family history of CRC exhibited significantly elevated ADR (47.6%) and ASDR (58.0%) in their 40s. Individuals with a family history should initiate colonoscopic examinations at 40 years of age.