Characteristics and Risk Factors of Interval Colorectal Advanced Adenomas after Negative Index Colonoscopy

Interval colorectal advanced adenoma (I-CRAA) carries insidious risk of interval colorectal cancer (I-CRC). The study aims to determine the frequency of I-CRAA after negative colonoscopy and discover the characteristics and the risk factors. Methods We retrospectively analyzed the information of the patients undergoing colonoscopy in the endoscopic center (2015-2019). Frequency of I-CRAA was calculated. The clinical features of I-CRAA were compared with sporadic colorectal advanced adenoma (Sp-CRAA). Results The frequency of I-CRAA was 0.71% (112/15759) per colonoscopy. I-CRAA was more likely to be located in the proximal colon (65.2% vs 34.8%, p<0.05) and has high pathological grade (5.4% vs 1.6%, p<0.05). are risk for I-CRAA (cid:0) p<0.05 (cid:0) . Excellent bowel preparation (OR 95% CI 2.425–5.73, p<0.001) and higher adenoma detection rate (OR 95% CI p = 0.012) are helpful for the detection of I-CRAA. I-CRAA found within 1 year other than or years after the initial colonoscopy were usually found by an endoscopist with higher ADR.


Introduction
Colorectal cancer (CRC) is one of the most common malignant tumors in humans, and the incidence in the Asia-Paci c region has increased rapidly in recent years [1] . Nearly half of patients have a survival time of less than 5 years due to late diagnosis and potentially advanced disease. Existing studies have shown that the identi cation of early lesions (adenomas) of CRC through colonoscopy and subsequent endoscopic resection can prevent disease progression, thereby reducing the incidence and mortality of CRC [2] . However, we often encounter some patients who has a negative initial colonoscopy and are diagnosed with CRC before the next recommended screening, which is de ned as interval colorectal cancer (I-CRC) [3] . I-CRC usually occurs within 6-36 months of the index colonoscopy, which reduces the effectiveness of CRC screening and gradually attracts everyone's attention.
The majority of CRC arise from adenoma, that is the classical adenoma-carcinoma sequence (ACS) [4] .
ACS is a series of events whereby colorectal adenomas develop, initially showing low grade dysplasia, from which some will progress to high grade dysplasia and eventually invasive carcinoma. The current studies are mostly limited to the interval cancer stage, and there is no relevant research on the interval advanced colorectal adenoma (I-CRAA), which is the precancerous stage of I-CRC. Therefore we will analyze the clinical features and risk factors of patients with I-CRAA in this study, so as to provide a new theoretical basis for the early prevention of colorectal tumors.

Research design
We retrospectively analyzed the detailed information of all patients undergoing colonoscopy at the Digestive Endoscopy Center of Beijing Tsinghua Changgung Hospital from January 2015 to December 2019. All colonoscopy examinations were completed by 10 endoscopists of the center. Patients who met the following criteria were included: (1) between the ages of 40 and 80; (2) patients who underwent colonoscopy again within 3 years after a negative index colonoscopy; (3) both colonoscopies reached the cecum. All negative colonoscopy including normal colonoscopy or non-cancerous lesions were completely excluded. The exclusion criteria were: (1) a history of colectomy for CRC or in ammatory bowel disease or familial adenomatous polyposis; (2) a history of CRC at index colonoscopy or incomplete histologic information. In order to compare the clinical and pathological characteristics of patients, patients with sporadic colorectal advanced adenoma (Sp-CRAA) who were examined at the same period in this center were also included in the study. This part of patients received colonoscopy for the rst time due to CRC screening.

De nition
The advanced adenoma includes tubular adenoma with diameter > 10 mm, villous or tubulovillous adenoma, any adenoma with high-grade dysplasia. I-CRAA is de ned as advanced adenoma diagnosed within 1-36 months after index negative colonoscopy. As a comparison, Sp-CRAA is de ned as advanced adenoma detected at the rst colonoscopy due to CRC screening, in which the patient had never undergone a colonoscopy before. Index colonoscopy is de ned as a negative colonoscopy performed prior to the diagnosis of advanced adenoma which including normal colonoscopy or non-cancerous lesions were completely excluded. We de ned the annual adenoma detection rate (ADR) for a physician as the proportion of annual (calendar year) screening colonoscopies where at least one adenoma (adenomatous polyp) was found. The quality of bowel preparation was evaluated using the Boston Bowel Preparation Scale (BBPS), and it was divided into excellent and good categories [5] .

Data Collection
We collected the basic information of the patients (age, gender, history of hypertension, diabetes, coronary artery disease and hyperlipidemia, family history of CRC, smoking and alcohol intake), colonoscopy report characteristics (follow-up time, operating endoscopist, bowel preparation quality, diverticulosis, lesion location, pathological classi cation). We divided the colon into the proximal (cecum, ascending colon, hepatic exure, transverse colon) and the distal (splenic exure, descending colon, sigmoid colon, rectum). The landmarks of the cecum were the appendiceal ori ce and ileocecal valve; hepatic exure was de ned as a gray-blue colored impression of the liver, splenic exure as a gray-blue colored impression of the spleen. During the study, all patients used polyethylene glycol electrolyte for bowel preparation.

Statistical Analysis
Continuous data were expressed as mean ± standard deviation and categorical data as number In patients with I-CRAA, 68.6% were men, and 42.9% were 60-69 years old at index colonoscopy. When I-CRAA patients were screened at index colonoscopy, only 33.9% of the patients had excellent bowel preparation quality, and half of the patients were performed by doctors with an ADR of less than 30%. 38.4% of patients had more than 3 polyps, and more than half of the patients had polyps in different intestinal segments. In addition, 64.3% of patients had a maximum adenoma diameter of more than 10 mm. (Table 1) Data are presented as number (%) We compared 112 patients with I-CRAA and 503 patients with Sp-CRAA (Table 2 and Table 3). There were no signi cant differences in gender and age between the two groups, but patients with I-CRAA have a higher probability of diabetes, smoking history, alcohol history, and family history of CRC (

Discussion
This study is the rst systematic study of the clinical features and risk factors of I-CRAA. It found that the frequency of I-CRAA was 0.71% per colonoscopy. Firstly, this nding suggests that the occurrence of interval lesions is more related to missed diagnosis, especially found within one year. Secondly, I-CRAA is more located in the proximal colon and related to diabetes, family history of CRC, smoking, drinking, and diverticulosis.
Colorectal cancer (CRC) is one of the leading causes of death in the world, and it usually develops through ACS sequences. Understanding the clinical characteristics and risk factors of this disease is an indispensable part of formulating an effective strategy to prevent CRC. Experts from all over the world have been committed to preventing I-CRC through population-based screening programs, but there are few studies on I-CRAA that are focused on interval precancerous lesions.
In recent years, a large number of studies in different countries show that I-CRC accounts for 2.6-10.3% of newly diagnosed CRC [6,7] . Kim et al. evaluated how often I-CRC could be detected by follow-up colonoscopy in clinical practice and they found that the rate of I-CRC detection during the surveillance period was at 0.09% [8] . In our study, 112 of 615 patients with CRAA were classi ed as I-CRAA, which accounted for 0.71% of the total number of examinations, and the detection rate of I-CRAA was much higher than I-CRC. In-time detecting and resecting the intermittent advanced adenoma is a major step for prevention of I-CRC and improve the patients' quality of life.
In terms of the clinical characteristics of patients, previous studies have shown that I-CRC is more common in women and elderly, which are considered to be risk factors [9,10] . However, in our study, I-CRAA were found in more male and elder patients, but the distribution difference was not statistically signi cant. Among them, the trend of gender distribution is similar to the results of several studies on I-CRC patients in Asian populations. They found that Asian male patients have a higher proportion of I-CRC, which shows that there is a possibility of racial difference in the occurrence of interval tumors and the differences may have emerged early in the tumor generation [8,11] . Our study also demonstrated that I-CRAA were more frequently detected in proximal colon, and more often manifests as a high-grade or sessile serrated adenoma, compared with Sp-CRAA. Our nding is in accordance with Samadder's study that most I-CRC appears in the proximal colon, and sporadic colorectal cancer is often found in the distal colon [12] . It suggests that interval tumors are more likely to occur in the proximal colon, more likely to have small and at nature and may result in limited effectiveness of colonoscopy in the proximal colon.
Thus, CRC risk reduction after a negative index colonoscopy was less pronounced for proximal lesions, especially in the caecum and ascending colon. In addition, in view of the fact that interval I-CRAA usually show high-grade dysplasia, we should pay more attention to improve the e ciency of lesion detection in proximal colon.
There are su cient evidences to prove that diabetes is an independent risk factor for I-CRC. The study of Laish et al. also found that cases with I-CRC had higher prevalence of diabetes [13,14] . Our study reveals the relationship between diabetes, diverticulosis and I-CRAA for the rst time. One explanation for the relationship between diabetes and CRC is that the hyperinsulinemia-induced increase in IGF-I bioactivity may promote the survival of transformed and mutated cells that would normally undergo apoptosis and increase the risk of CRC eventually [15] . This mechanism may have played a role in the early stage of ACS sequence. The research of Hou et al. also indicates that metformin therapy is correlated with a signi cant decrease in the risk of CRC and advanced adenoma in type 2 diabetic patients [16] . Using a populationbased cohort from Canada, Bressler and colleagues found that diverticulosis was documented in 38% of I-CRC, compared to only 7% in detected CRC [17] . On one hand, the presence of diverticulum may interfere with the ability to recognize precancerous and malignant lesions at colonoscopy [18] . On the other hand, the high pressure in the colon that causes diverticulosis can prolong the time that the mucosa is in contact with potential carcinogens [19] However, a meta-analysis demonstrated that diverticulosis was not associated with an increased risk of advanced colorectal neoplasia [20] Thus, it is necessary to conduct a prospective cohort study to elucidate not only the association of diverticulosis with colorectal neoplasia but also the causality. In addition, we found that smoking and alcohol history are risk factors for I-CRAA, and if the patient's family has CRC, the risk of I-CRAA is also higher.
I-CRC can be divided into three subcategories: 1) missing sporadic colorectal cancer (Sp-CRC) and precancerous lesions; 2) incomplete resection of precancerous lesions; 3) de novo I-CRC that arise rapidly due to abnormal molecular biology [21] . However, the role of its biological characteristics has not yet reached consensus during the formation of I-CRC, and most of them are believed to be caused by missing or incompletely removed precancerous lesions [22] . Therefore, the incidence of I-CRC is also considered to be a key indicator of the quality of colonoscopy in medical institutions and endoscopists. Previous studies have shown that an endoscopist's ADR is a powerful indicator of their skill in performing colonoscopy, with a proven inverse association with I-CRC [23] . The study showed that patients with endoscopists whose ADR > 33% had a 57% lower risk of developing I-CRC than those with ADR < 19% [24] . Consequently, ADR has become the key quality indicator for colonoscopy. Our research on I-CRAA found that patients with the index colonoscopy are usually completed by a doctor with a lower ADR, their bowel preparation is relatively poor, the diameter of the lesion is relatively large, and the lesions are usually found in more than one colon segments. Interestingly, according to the detecting time, the I-CRAA is divided into 1-year, 2-year and 3-year periods after index colonoscopy. It can be found that the index colonoscopy was usually performed by endoscopists with lower ADR and the diagnostic colonoscopy was usually performed by endoscopists with higher ADR for the I-CRAA found within 1-year period. This association was not statistically signi cant for I-CRAA detected in 2-year and 3-year periods. In addition, we also found that there was no signi cant difference in the quality of bowel preparation between the index and diagnostic colonoscopy within the same patient. This nding suggests that early I-CRAA is more likely to be caused by missing than late I-CRAA, which may be more relevant to the skill of endoscopists.
The limitation of this study is that it was a single center retrospective study that only represents the characteristics of the population in a limited region. Although we have collected all the information in the patients' medical record system, there are still some patient-related factors potentially related to the risk of interval tumor, such as obesity, diet or physical activity, were not available. In the future, we will analyze the clinical features and risk factors of interval tumors through further prospective research.
In conclusion, I-CRAA has its unique clinical characteristics, and its occurrence is more related to lowquality colonoscopy. It is worthy of special attention for the prevention of CRC.