Synchronous Neoplasia Rates at Colonoscopic Diagnosis of Early-Onset vs Average-Onset Colorectal Cancer

Key Points Question At colonoscopic diagnosis of colorectal cancer, do patients with early-onset vs average-onset of disease have different rates of synchronous colorectal neoplasia? Findings In this cross-sectional study of 300 patients, patients with early-onset colon cancer, but not rectal cancer, had significantly higher rates of synchronous advanced adenomas compared with patients with average-onset cancers. Meaning The finding of increased synchronous advanced adenomas among patients with early-onset colon cancer, but not rectal cancer, suggests widespread field cancerization in the former, indicating biological differences by primary tumor site.


Introduction
Colorectal cancer (CRC) remains the third most common cancer and is the third leading cause of cancer-related mortality in the United States. 1 Although the incidence of CRC continues to decrease among adults older than 50 years, likely due to population-based screening with colonoscopy, 1-4 the incidence among adults younger than 50 years has steadily increased by 2% annually since the 1990s. 5 Early-onset CRC, defined as diagnosis at an age younger than 50 years, currently accounts for 10% of all cases of CRCs 5,6 and is estimated to account for 1 in 10 cases of colon cancer and 1 in 4 cases of rectal cancer by 2030. 7 Primary tumors in early-onset CRC are located predominantly in the distal colon and rectum compared with average-onset CRC, [8][9][10] with rectal cancer being most frequent in the US. [8][9][10] Patients with early-onset CRC often experience a delay in diagnosis, 9,11 which may account for their more advanced stage at presentation, although a more aggressive biology is suggested. 9 Most cases of early-onset CRC are sporadic, and a prospective study of early-onset CRCs identified germline variants in 16% of patients, of whom approximately one-half had Lynch syndrome. 12 Although synchronous adenomas are often present at diagnosis among patients with CRC, sparse data exist for patients with early-onset CRC. [13][14][15] Such data can provide insight into field cancerization 16 and risk of metachronous neoplasia. 17 In a study of 1522 patients with CRC, synchronous colorectal neoplasms were observed in 505 patients (33%). 13,14 Colonoscopy enables the removal of established CRC precursor lesions, including adenomas, advanced adenomas, and sessile serrated lesions. 18 Patients with an advanced adenoma had a 2.5-fold greater risk of subsequent development of CRC compared with those without an adenoma. 19 Serrated lesions can progress through the serrated neoplasia pathway characterized by a variant in BRAF (V600E) (OMIM 164757), disruptions in Wnt signaling, and widespread CpG island methylation. 20,21 We examined synchronous neoplasia at colonoscopic diagnosis of early-onset CRC compared with average-onset CRC given the potential insights into field cancerization and risk of metachronous CRC. We sought to test the hypothesis that patients with early-onset CRC may have lower rates of synchronous neoplasia given that adenoma prevalence increases substantially with age. 22,23 We also examined synchronous neoplasia in association with primary cancer location (ie, colon vs rectum) given differences in their biology, which may affect findings at colonoscopy. 8,9 Methods Patients with primary early-onset colon and rectal adenocarcinomas (age at diagnosis, 18-49 years) seen at Mayo Clinic sites (Rochester, Minnesota; Jacksonville, Florida; and Scottsdale, Arizona) or the Mayo Health System from January 1, 2012, to December 31, 2022, were identified from the electronic health record (EHR) using Epic Slicer Dicer. The patient list was exported, random numbers were generated and assigned for each case, and cases were sorted numerically using Excel software, version 2021 (Microsoft Corp). Each patient's EHR was then reviewed based on strict inclusion and exclusion criteria until we met the projected sample size (see Statistical Analysis). Eligible patients had optical (high-definition white light) colonoscopy to the cecum with at least fair bowel preparation, with diagnosis of CRC confirmed by histopathologic findings. Exclusion criteria included patients with inflammatory bowel disease, known familial adenomatous polyposis or Lynch syndrome, 10 or more polyps at index colonoscopy, or prior CRC. A total of 150 patients with earlyonset CRC were matched with patients with average-onset colon cancer (n = 75) and rectal cancer (n = 75) based on sex and indication for colonoscopy because these factors are known to influence colonoscopic findings. 24,25 Matching cases for patients with early-onset CRC were identified by consecutive review of a list of randomly selected patients with average-onset CRC until an equivalent number of matched cases was obtained. The relative proportion of early-onset to average-onset CRC cases was similar across study sites. This study was reviewed and approved by the Mayo Clinic institutional review board, which waived patient consent because this was a retrospective analysis of deidentified data. The study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for observational studies.
Data on synchronous neoplasia size, number, and location in the colorectum were abstracted from colonoscopy and related pathology reports that recorded histopathologic interpretation of biopsy or polypectomy specimens. Synchronous neoplasia included adenomas, advanced adenomas (Ն1 cm, villous histologic characteristics, and/or high-grade dysplasia) and sessile serrated polyps.
Hyperplastic polyps were excluded from the study analysis given their lack of neoplastic potential. 21 Data were collected for DNA mismatch repair ( Body mass index (BMI) and family history of CRC (first-and second-degree relatives) were abstracted from the EHR. Symptoms at diagnosis of CRC were also recorded.

Statistical Analysis
Data on synchronous neoplasia number, size, site, and histopathologic characteristics were compared between patients with early-onset colon cancer and patients with early-onset rectal cancer and with their respective matched cohorts with average-onset CRC. Based on our study hypothesis, we assessed and compared rates of synchronous neoplasia between groups. Sample size calculations indicated that 75 patients per group (total, 150) provided 80% power to detect a 20% difference in the rate of synchronous neoplasia between patients with early-onset CRC and patients with average-onset CRC at a 2-sided α of .10, which we regarded as a clinically meaningful difference.
Our estimate for prevalence of synchronous adenomas (33%) was based on the literature. 14 Continuous variables are described as median (IQR) values and were compared using the Mann-Whitney test. The Fisher exact test was used to compare categorical variables exclusively due to sample size. Two-sided P values are reported, and P < .05 was considered statistically significant for all analyses. Statistical analysis was performed with R studio software, version 2022.02.3 (R Group for Statistical Computing).
Primary cancers in the left colon were more common among patients with early-onset colon cancer compared with those with average-onset colon cancer (38 [51%] vs 24 [32%]; P = .02). Body mass index was similar between patients with early-onset and average-onset colon cancer (P = .15).
At cancer diagnosis, TNM stage and tumor molecular markers (MMR, BRAF V600E , or KRAS) did not differ significantly between patients with early-onset and patients with average-onset colon cancer (Table 1). No differences were found for patient-reported family history of CRC in our study population in which patients with familial adenomatous polyposis or Lynch Syndrome had been excluded. Among patients who had germline genetic testing, such testing was more frequent for At colonoscopic diagnosis of colon cancer, at least 1 synchronous adenoma was found in 42 patients with early-onset disease (56%) and 35 patients with average-onset disease (47%) ( Table 2).

JAMA Network Open | Oncology
The median adenoma size was significantly larger in patients with early-onset-colon cancer compared with those with average-onset colon cancer (10 mm [IQR, 7-14 mm] vs 5 mm [IQR, 4-7 mm]; P = .001) ( Table 2). Advanced adenomas were significantly more common in the early-onset [13%]; P < .001), and they were more common in the left colon (Figure 1), which was maintained when the cohort was limited to pMMR tumors (P = .001).  (Figure 2). Of the 11 patients with early-onset rectal cancer with advanced adenoma, 4 had germline testing, and no PGVs were found.
Similarly, 5 of 14 patients with average-onset rectal cancer with advanced adenoma had germline testing, and no PGVs were identified. A total of 21 of 136 symptomatic patients with rectal cancer (15%) had advanced adenoma. The frequency of sessile serrated polyps did not differ significantly between these groups ( Table 2).  27 Among the 10 patients with average-onset colon cancer and advanced adenomas, 3 had germline testing data, and 1 had a monoallelic MUTYH variant. Although germline data were available for only a subset of patients, such data do not suggest an explanation for the increase in advanced adenomas among patients with early-onset vs average-onset colon cancer.

Colon vs Rectal Cancer
Colon and rectal cancers were analyzed separately given their purported biological differences and the fact that most cases of early-onset cancers arise in the rectum in the US population. 8-10 In  Field cancerization describes a field of cellular and molecular alterations that predispose the individual to the development of colorectal neoplasia. 35 We observed increased synchronous neoplasia throughout the colorectum in patients with early-onset colon cancers, suggestive of extended field cancerization whereby events involved in carcinogenesis occur in normal-appearing tissue away from a cancer that can progress to precursor lesions. 16 Our data suggest that such field cancerization may be more limited among patients with early-onset rectal cancer, for whom the distribution of adenomas was more limited to the distal colorectum. Multiple etiologic factors, including dietary, lifestyle, microbial, and genetic variables, exert their influence and interactions to contribute to field cancerization and susceptibility to neoplastic development and progression.
Future research in early-onset CRC is needed to identify endogenous and environmental exposures that can influence the genome, epigenome, transcriptome, proteome, and microbiome or metabolome in addition to host immunity.

Limitations and Strengths
This study has some limitations. It excluded patients with obstructing tumors because complete colonoscopy was not feasible and was required for eligibility. This requirement may have contributed to the higher number of right-sided cancers in our series compared with other reports. 8,9 Other limitations included the retrospective nature of our study, incomplete germline genetic testing for all

Rectum
Among patients with early-onset or average-onset rectal cancer, the percentages of those with adenoma (A and B) or advanced adenoma (C and D) by site within the colorectum are shown. Although adenoma distribution was similar by age group, advanced adenomas were significantly more common in the rectum among early-onset compared with average-onset rectal cancers (45% vs 7%; P < .001).
early-onset CRC cases, potential referral or other selection bias, and the relatively small study sample size such that validation of our study findings in a larger cohort is clearly warranted.
This study also has some strengths, including strict eligibility criteria of complete colonoscopy with adequate bowel preparation, exclusion of known hereditary syndromes or polyposis, recorded family history information, and germline genetic testing data when available. Patients were randomly selected and matched based on relevant factors of sex and indication for colonoscopy; patients with colon cancer and patients with rectal cancer were analyzed separately. Colonoscopies were performed both at Mayo Clinic sites or outside prior to referral.

Conclusions
In our cross-sectional study, we observed a significant increase in the number of synchronous advanced adenomas distributed throughout the colon among patients with early-onset compared with average-onset colon cancer, suggesting extended field cancerization. Accordingly, patients with early-onset colon cancer are at increased risk of synchronous and metachronous CRC, and future studies that examine rates of metachronous neoplasia are needed. Among patients with early onsetrectal cancer, however, synchronous neoplasia was not increased compared with those with average-onset rectal cancer, suggesting differences in their pathobiology.