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High frequency of colorectal neoplasia in patients with sporadic adenomas or adenocarcinomas of the papilla of Vater: The same adenoma-carcinoma sequence?

  • Author Footnotes
    1 These authors contributed equally to this work.
    Fan Zhou
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Lu He
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    1 These authors contributed equally to this work.
    Affiliations
    Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Ying Xie
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Dehua Tang
    Affiliations
    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Meng Zhang
    Affiliations
    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Ying Lv
    Affiliations
    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Guifang Xu
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    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Xiaoping Zou
    Correspondence
    Corresponding authors.
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    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Lei Wang
    Correspondence
    Corresponding authors.
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    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Chunyan Peng
    Correspondence
    Corresponding authors.
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    Department of Gastroenterology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open AccessPublished:November 18, 2022DOI:https://doi.org/10.1016/j.dld.2022.10.022

      Abstract

      Background

      Data on the frequency of colorectal neoplasia in sporadic ampullary tumors remains scarce.

      Methods

      We retrospectively reviewed 135 patients undergoing endoscopic ampullectomy from January 2018 to July 2021, and identified 95 patients with sporadic ampullary adenoma who underwent total colonoscopy. Colonoscopy findings were compared with 380 asymptomatic controls using the chi-squared test. Whole-exome sequencing (WES) was performed on one patient with synchronous adenomas of the ampulla of Vater and ascending colon.

      Results

      Colorectal polyps were present in 60% of Cases vs. 34.7% of Controls (P = 0.001), advanced adenoma in 20% vs. 5.5%, and adenocarcinoma in 4.2% vs. 0.8%. Cases tended to have larger polyps than Controls (P<0.001), while there was no difference in polyp location and histology between the two groups. The odds ratio of all the colorectal lesions, advanced colorectal adenoma and adenocarcinoma in Cases was 1.7, 4.2, and 4, respectively. WES in one patient revealed that both of ampullary adenoma and colonic adenoma shared somatic ABCB1 mutation.

      Conclusions

      The frequency of colorectal polyps or neoplasia was significantly higher in Cases than Controls. We proposed that ampullary neoplasia is analogous to colon lesions and warrants total colonoscopy screening in patients diagnosed with ampullary tumors.

      Keywords

      1. Introduction

      Adenomas of the papilla of Vater, also known as ampullary adenomas, account for 5–7% of periampullary tumors and 0.2% of all gastrointestinal cancers, respectively [
      • Campbell Jr., D.R.
      • Lee J.H
      A comprehensive approach to the management of benign and malignant ampullary lesions: management in hereditary and sporadic settings.
      ,
      • Martin J.A.
      • Haber G.B.
      Ampullary adenoma: clinical manifestations, diagnosis, and treatment.
      . Ampullary adenoma can emerge sporadically or genetically, such as familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and von Recklinghausen's disease [
      • Deschamps L.
      • Dokmak S.
      • Guedj N.
      • et al.
      Mixed endocrine somatostatinoma of the ampulla of vater associated with a neurofibromatosis type 1: a case report and review of the literature.
      ]. These patients not only suffer from multiple colon adenomas but also bear an increased lifetime risk of periampullary tumors. It has been reported that 50–65% of patients with FAP had adenomatous polyps of the duodenum or the ampulla [
      • Parc Y.
      • Piquard A.
      • Dozois R.R.
      • et al.
      Long-term outcome of familial adenomatous polyposis patients after restorative coloproctectomy.
      ].
      The pathogenesis of sporadic ampullary adenoma remains unclear. Numerous studies supported the idea that ampullary adenoma progress through an adenoma to carcinoma sequence. From histological observation, Kaiser et al. [
      • Kaiser A.
      • Jurowich C.
      • Schonekas H.
      • et al.
      The adenoma-carcinoma sequence applies to epithelial tumours of the papilla of Vater.
      ] have confirmed the transition from adenoma with mild, moderate, and severe atypia to invasive adenocarcinoma, which is analogous to the development of colon cancer. Several case series [
      • Awadie H.
      • Klein A.
      • Tate D.
      • et al.
      The prevalence of small-bowel polyps on video capsule endoscopy in patients with sporadic duodenal or ampullary adenomas.
      ,
      • Maruoka D.
      • Arai M.
      • Ishigami H.
      • et al.
      Sporadic nonampullary duodenal adenoma/carcinoma is associated with not only colon adenoma/carcinoma but also gastric cancer: association of location of duodenal lesions with comorbid diseases.
      ,
      • Sharaiha R.Z.
      • Cohen M.S.
      • Reimers L.
      • et al.
      Sporadic duodenal adenoma and association with colorectal neoplasia: a case-control study.
      ,
      • Dariusz A.
      • Jochen R.
      Increased prevalance of colorectal adenoma in patients with sporadic duodenal adenoma.
      ,
      • Lagarde S.
      • Dauphin M.
      • Delmas C.
      • et al.
      Increased risk of colonic neoplasia in patients with sporadic duodenal adenoma.
      ] have revealed a significantly higher risk of colonic polyps in patients with sporadic non-ampullary duodenal adenomas. However, there is a lack of data regarding the association between sporadic adenomas of the Papilla of Vater and colon neoplasia. Our study aimed to estimate the prevalence of colorectal neoplasia in patients with sporadic ampullary adenomas and adenocarcinomas, and to preliminarily elucidate the possible molecular mechanism of concurrent ampullary and colon lesions by whole-exome sequencing (WES).

      2. Materials and methods

      2.1 Study design

      This was a single-center, retrospective case-control study conducted at Nanjing Drum Tower Hospital, China, between January 2018 and July 2021. This study was approved by the Institutional Review Board of Nanjing Drum Tower Hospital.

      2.2 Patients and data

      We searched all ampullary adenoma or adenocarcinoma cases in the electronic endoscopy databank stored in the Department of Gastroenterology of Nanjing Drum Tower Hospital. All clinical, endoscopic, and histologic reports were retrieved. Inclusion criteria were: (1) patients with ampullary adenoma or adenocarcinoma confirmed by both endoscopy and histology; (2) patients with total colonoscopy during the diagnosis of ampullary neoplasm or within one year (one year before or one year after). Exclusion criteria were: personal or family history of familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), MUTYH-associated polyposis (MAP), von Recklinghausen's disease, or familial colorectal cancer.
      Prevalence of colorectal neoplasia in the Cases group was compared with the colonic findings in 380 age- and sex-matched (1:4) asymptomatic control patients (Controls) who underwent both gastroscopy and colonoscopy during 2018 and 2021 at our center (n = 23,532). To reduce the selection bias of patient between the two groups, Propensity Score Matching (PSM) [
      • Austin P.C.
      An introduction to propensity score methods for reducing the effects of confounding in observational studies.
      ] was conducted based on a linear model with a caliper value of 0.02 through one-to-one nearest neighbor matching (1:4). We performed PSM with Matching package (version 4.10–2) using R software (version 4.2.1). The clinical, endoscopic, and pathological data of each included patient were recorded in detail. Clinical features included demographics, symptoms and durations, indications for colonoscopy. The location, size, and histology of ampullary and colorectal neoplasia were also collected. The histopathology of ampullary and colorectal neoplasia included tubular, tubulovillous and villous adenoma with/without low- and high-grade dysplasia, as well as carcinoma, according to Vienna classification [
      • Schlemper R.J.
      • Riddell R.H.
      • Kato Y.
      • et al.
      The Vienna classification of gastrointestinal epithelial neoplasia.
      ]. Patients with multiple lesions were classified according to the most advanced lesion. Advanced colorectal adenomas were defined as: size ≥10 mm, tubulovillous (villous component >20%) or villous histology, and/or high-grade dysplasia [
      • Atkin W.S.
      • Morson B.C.
      • Cuzick J.
      Long-term risk of colorectal cancer after excision of rectosigmoid adenomas.
      ].

      2.3 Whole exome sequencing and variant analysis

      Genomic DNA (gDNA) was extracted from peripheral blood, the ampullary adenoma and the colon polyp from one patient. WES was performed by BGISEQ-500 (BGI, China). The clean data for each sample was mapped to the human reference genome (GRCh38/HG38) using the Burrows-Wheeler Aligner (BWA) (Oxford, England). We sequenced an average of 226,394,835 reads for each sample after reads quality filtering and duplication removing. The sequencing depths for blood and tissues were 197X on average.
      Candidate gene mutations, including SNV, Indel and CNV, were screened using GATK [
      • DePristo M.A.
      • Banks E.
      • Poplin R.
      • et al.
      A framework for variation discovery and genotyping using next-generation DNA sequencing data.
      ]. Germline mutations of this case were compared with CGC database (Cancer Gene Census) to identify candidate cancer susceptibility genes. Somatic mutations for ampullary adenoma and colon polyp were distinguished from germline mutations. Somatic SNVs and Indels were detected using GATK MuTect2 tool, and were annotated with GATK Funcotator. Somatic CNVs were detected using FACETS software [
      • Shen R.
      • Seshan V.E.
      FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing.
      ], and were annotated by Ensemble VEP [
      • McLaren W.
      • Gil L.
      • Hunt S.E.
      • et al.
      The Ensembl variant effect predictor.
      ]. Tumor driver genes were compared with IntOGen, CGC and pan-cancer database [
      • Kandoth C.
      • McLellan M.D.
      • Vandin F.
      • et al.
      Mutational landscape and significance across 12 major cancer types.
      ]. Homology of somatic mutaions was compared with BAM-matcher [
      • Wang P.P.
      • Parker W.T.
      • Branford S.
      • et al.
      BAM-matcher: a tool for rapid NGS sample matching.
      ].

      2.4 Statistical analysis

      Data submitted for statistical testing were analyzed with the Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL, version 25.0). Data are presented as median and range or as mean with standard deviation (SD). Outcomes in cases and controls were compared using the chi-squared test or Fisher's exact tests, when appropriate. Odds ratio (OR) and 95% confidence intervals (CI) of the rates in two groups were calculated using conditional logistic regression with SAS software (SAS Institute, Cary, NC, version 9.4). Two-sided P values of less than 0.05 were considered statistically significant.

      3. Results

      3.1 Demographics and baseline characteristics

      Between January 2018 and July 2021, 135 patients with suspected ampullary adenoma or adenocarcinoma were referred to our center and underwent endoscopic resection. All patients without a colonoscopy within one year were recommended to taking once. Finally, a total of 95 patients were included in this study (Fig. 1). 32 patients did not have a colonoscopy, 3 patients suffered from FAP, 5 patients were not diagnosed with adenoma or adenocarcinoma microscopically and they were thus excluded from the study. As for controls, we searched our digital endoscopic databank, and those who received both gastroscopy and colonoscopy were included to finally select 380 age- and sex-matched controls (1:4). The mean age in both groups was 57 years old (range: 19–83 years old), and the male/female ratio was 1:0.7 (Table 1).
      Table 1The clinical characteristics of case patients and control patients.
      Clinical characteristicsCases (n = 95)Controls (n = 380)
      Age (years), mean ±SD57.7 ± 11.757.7 ± 11.7
      Sex (% male)58.958.9
      Indication (%)
       Health checkup78 (82.1)157 (41.3)
      Functional gastrointestinal disorder8 (8.4)89 (23.4)
       FOBT Positive4 (4.2)12 (3.1)
       Ulcerative colitis3 (3.1)0
       Jaundice1 (1.0)0
       Hemorrhoid1 (1.0)0
       Follow-up0119 (31.3)
       Ascites03 (0.8)
      Index lesion size (cm), mean (range)1.37 (0.5–5)NA
       <1 cm (%)25 (26.3)
       1–2 cm (%)61 (64.3)
       ≥2 cm (%)9 (9.4)
      FOBT: fecal occult blood test; NA: not available.

      3.2 Cases (Sporadic ampullary tumors)

      The most common indication for colonoscopy in Cases was routine health check-up (82.1%), followed by functional gastrointestinal disorder (8.4%), positive fecal occult blood test (4.2%), ulcerative colitis (3.1%), jaundice (1.0%) and hemorrhoid (1.0%). The mean size of ampullary lesions was 1.37 cm (range 0.5–5 cm). Most patients had large (≥1 cm) ampullary adenomas (n = 70, 73.7%). In terms of histology, 86 patients were identified with adenomas and 9 patients with adenocarcinomas (Supplementary Table 1). Among 86 patients with ampullary adenomas, 25.2% (n = 24) had tubulovillous adenomas. There was no association between ampullary carcinoma and gender (P = 0.480) or age (P = 0.151).

      3.3 Controls

      Altogether, 380 controls were matched to analyze the frequency of colorectal neoplasia in our center. Their indications for endoscopy included health check-up (41.3%), functional gastrointestinal disorder (23.4%), follow-up for gastritis or ESD procedure (31.3%), positive fecal occult blood test (3.1%), and ascites (0.8%).

      3.4 Colonoscopy findings

      Colorectal neoplasia of any histology, including hyperplastic polyps, adenomas, and carcinomas, was observed in 60% of Cases (ampullary tumor patients, n = 95), compared with that found in Controls (n = 132, 34.7%), which is consistent with the rate of our population [
      • Meng T.
      • Chen X.
      • Lu J.H.
      • Zhang L.B.
      • Chen H.H.
      Comparative study of colonic polyp detection rate between ordinary population and high risk population.
      ] (Table 2). Patients with ampullary tumors were 1.7 times more likely to have all kinds of colorectal neoplasia (95% CI: 1.3–2.4, P = 0.001). Furthermore, the prevalence of advanced colorectal adenoma was significantly higher in Cases (20%) than in Controls (5.5%), with an odds ratio of 4.2 (95% CI = 2.2–8.2, P < 0.001). However, there was no significant difference in the frequency of colorectal carcinoma between the two groups (OR=4, 95% CI = 0.8–19.8, P = 0.09) (Fig. 2).
      Table 2The distribution of size, histology, and location of colorectal lesions in both groups.
      Cases (n = 139 polyps)Controls (n = 310 polyps)P value
      Size<0.001
        1–5mm84 (60.4%)246 (79.3%)
        6–10mm40 (28.7%)46 (14.8%)
        >11mm15 (10.8%)18 (5.8%)
      Location0.105
        Ascending colon30 (21.6%)68 (21.9%)
        Transverse colon32 (23%)62 (20%)
        Descending colon26 (18.7%)40 (12.9%)
        Sigmoid colon38 (27.3%)83 (26.7%)
        Rectum13 (9.35%)57 (18.4%)
      JNET classification0.056
        140 (28.7%)68 (21.9%)
        2A89 (64%)232 (74.8%)
        2B6 (4.3%)7 (2.3%)
        34 (2.9%)3 (1%)
      Histology, n (%)0.108
       Hyperplastic polyp37 (26.6%)114 (36.8%)
       Tubular adenoma92 (66.2%)180 (58%)
       Sessile serrated polyp04 (1.3%)
       Vilous component6 (4.3%)8 (2.6%)
       Carcinoma4 (2.9%)3 (1.0%)
       Others01 (0.3%)
      Fig 2
      Fig. 2The odds ratios for colorectal lesions in sporadic ampullary adenomas and matched controls.
      In Cases, there were 139 polyps found with 84 polyps (60.4%) of 1–5 mm, followed by 40 polyps (28.7%) of 6–10 mm and 15 polyps (10.8%) larger than 1 cm (Table 2). While in Controls, the rate was 79.3%, 14.8%, and 5.8%, respectively, which was significantly lower overall than that in Cases (P<0.001). Although we observed a tendency of more lesions with JNET type 2B and 3 in Cases, and a strong association of JNET classification and histology, there was no significant differences in both groups concerning polyp location, JNET classification [
      • Sano Y.
      • Tanaka S.
      • Kudo S.E.
      • et al.
      Narrow-band imaging (NBI) magnifying endoscopic classification of colorectal tumors proposed by the Japan NBI Expert Team.
      ] and histology (P = 0.105, P = 0.056, P = 0.108, respectively).

      3.5 Germline and somatic mutations of one patient with synchronous adenoma of the ampulla of Vater and ascending colon

      A 61-year-old male patient presented with abdominal distention for three months. His gastroscopy and histopathology showed ampullary adenoma with low grade dysplasia (1.5 cm*1.0 cm), and colonoscopy showed one 0.3 cm*0.3 cm colon adenoma in ascending colon (Fig. 3). The ampullary adenoma, but not the colonic adenoma, was within the advanced adenoma criteria. The whole-exome sequencing was performed on his peripheral blood, ampullary adenoma and colon adenoma (Supplementary Table 2). We identified 124,093 SNPs in the three samples on average, and 1769 novel SNPS were identified. Among all the coding regions, there was an average of 10,491 synonymous SNPs, 10,256 missense SNPs, 40 stop-loss SNPs, 113 stop-gain SNPs, 32 start-loss SNPs and 158 splice-site SNPs. The Ti/Tv of coding SNPs was 3.0 (Table 3).
      Fig 3
      Fig. 3One patient diagnosed with synchronous adenoma of the ampulla of Vater and ascending colon. (A-B) The endoscopic view of the adenoma of the papilla of Vater. (C) Microscopically, the ampullary adenoma was a tubular adenoma with low-grade dysplasia. (D-E) The endoscopic view of the adenoma in the ascending colon. (F) Microscopically, the colonic lesion was a tubular adenoma.
      Table 3Functional categories for coding SNPs.
      SampleSynonymousMissenseStopgainStoplossStartlossSplicingTi/Tv
      Average10,49110,25611340321583.00
      Ampullary10,49610,27611540331582.99
      Blood10,51110,28811140311602.99
      Colon10,46810,20611440321583.01
      Germline mutations detected by this patient's peripheral blood were compared with Cancer Gene Census database, and the cancer susceptibility genes included ALK, BARD1, KDR, FAT1, WRN, PTCH1, HNF1A, BRCA1 and SETBP1 (Supplementary Table 4). Somatic mutations of both ampulla and colon adenoma were compared with known driver gene database (Supplementary Table 5). In ampullary adenoma, the driver genes detected included ABCB1, BRAF, CTNNB1, CTNND1, MN1, NCOR1, PIK3CB, PRX, PTPN13, RANBP2, RBM10, SMARCA4, SMARCAD1, SMC3, STAT3, SYNE1, and ZNF703. While for early-staged colon adenoma, only somatic QKI, ABCB1 and GOLGA5 were detected perhaps. Somatic cell homology test showed ampullary adenoma and colon adenoma were homologous (Supplementary Table 6).

      4. Discussion

      This study is, up to now, the largest-scale case-control study to assess the risk of colorectal neoplasia in patients with ampullary adenoma or adenocarcinomas. We found that the frequency of colorectal polyps of all histology and advanced colorectal adenomas was significantly higher in the ampullary tumor group when compared to matched controls. Besides, there was a trend towards higher risks of colorectal adenocarcinoma in Cases (P = 0.09), which was possibly due to the small number of positive cases. Finally, through whole-exome-sequencing of one patient with both ampullary and colon adenoma, we identified BRCA1 germline mutation and somatic ABCB1 mutation in the two adenomas.
      Apel et al. [
      • Apel D.
      • Jakobs R.
      • Weickert U.
      • et al.
      High frequency of colorectal adenoma in patients with duodenal adenoma but without familial adenomatous polyposis.
      ] firstly focused on the risk of colorectal adenoma in patients with sporadic non-ampullary duodenal adenomas in 2004. They found that 16 out of 22 patients (72.7%) with duodenal adenomas had colorectal adenomas, which was significantly higher than that observed in the general population (29%−42%). Meanwhile, an Australian study [
      • Murray M.A.
      • Zimmerman M.J.
      • Ee H.C.
      Sporadic duodenal adenoma is associated with colorectal neoplasia.
      ] also confirmed that all the colorectal neoplasias were significantly more common in the duodenal adenoma group than matched controls (56% vs. 33%). And several studies [
      • Awadie H.
      • Klein A.
      • Tate D.
      • et al.
      The prevalence of small-bowel polyps on video capsule endoscopy in patients with sporadic duodenal or ampullary adenomas.
      ,
      • Maruoka D.
      • Arai M.
      • Ishigami H.
      • et al.
      Sporadic nonampullary duodenal adenoma/carcinoma is associated with not only colon adenoma/carcinoma but also gastric cancer: association of location of duodenal lesions with comorbid diseases.
      ,
      • Ramsoekh D.
      • van Leerdam M.E.
      • Dekker E.
      • et al.
      Sporadic duodenal adenoma and the association with colorectal neoplasia: a case-control study.
      ,
      • Chung W.C.
      • Lee B.I.
      • Roh S.Y.
      • et al.
      Increased prevalence of colorectal neoplasia in korean patients with sporadic duodenal adenomas: a case-control study.
      later also reported the same phenomenon, with rates of all colorectal neoplasia in the duodenal adenoma group and control group ranging from 42% to 61%, 17% to 37%, respectively. However, the studies mentioned above all discussed patients with duodenal adenomas, which included both ampulla and extra-ampulla lesions. In 2005, a German study [
      • Schneider A.R.
      • Seifert H.
      • Trojan J.
      • et al.
      Frequency of colorectal polyps in patients with sporadic adenomas or adenocarcinomas of the papilla of vater–an age-matched, controlled study.
      ] specifically studied the patients with ampullary adenoma and found no difference in the frequency of colorectal polyps in cases and controls, with rates of 23% and 26%, respectively. Nevertheless, the risk of colorectal polyps of all histology among ampullary tumors (Cases) and Controls in our study was 60% vs. 34.7%, which was much higher than the German study. It might be attributed to a larger sample size and better endoscopic diagnostic technology.
      In terms of location of colorectal polyps, several studies [
      • Sharaiha R.Z.
      • Cohen M.S.
      • Reimers L.
      • et al.
      Sporadic duodenal adenoma and association with colorectal neoplasia: a case-control study.
      ,
      • Dariusz A.
      • Jochen R.
      Increased prevalance of colorectal adenoma in patients with sporadic duodenal adenoma.
      ,
      • Schneider A.R.
      • Seifert H.
      • Trojan J.
      • et al.
      Frequency of colorectal polyps in patients with sporadic adenomas or adenocarcinomas of the papilla of vater–an age-matched, controlled study.
      reported that patients with ampullary tumors or duodenal adenomas tended to have a higher possibility of proximal colon polyps (proximal to the splenic flexure), ranging from 50 to 90%. However, our study and a recent Australian study [
      • Awadie H.
      • Klein A.
      • Tate D.
      • et al.
      The prevalence of small-bowel polyps on video capsule endoscopy in patients with sporadic duodenal or ampullary adenomas.
      ] found no difference in colorectal polyp location between the duodenal adenoma group and Controls. It was reported that distal colorectal lesions follow the traditional adenoma-adenocarcinoma sequence and often have APC mutations [
      • Huang Y.
      • Duanmu J.
      • Liu Y.
      • et al.
      Analysis of multi-omics differences in left-side and right-side colon cancer.
      ], while proximal lesions are more prone to have microsatellite instability (MSI), BRAF mutation, and SMAD mutations [
      • Klose J.
      • Kloor M.
      • Warschkow R.
      • et al.
      Does side really matter? Survival analysis among patients with right- versus left-sided colon cancer: a propensity score-adjusted analysis.
      ]. Sessile serrated lesions (SSLs) and traditional serrated adenomas, considered to be premalignant, were known to be mainly located in the proximal colon with “mucus cap”, indistinct borders, and a cloud-like surface [
      • Crockett S.D.
      • Nagtegaal I.D.
      Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia.
      ,
      • Nishizawa T.
      • Yoshida S.
      • Toyoshima A.
      • et al.
      Endoscopic diagnosis for colorectal sessile serrated lesions.
      . In our study, four sessile serrated polyps were observed in Controls, but not in Cases. As patients in Controls were chosen from the same period of ampullary adenoma patients, it was unlikely to be ascribed to the unawareness of these lesions under current endoscopic diagnostic technology. Additionally, Edelstein et al. [
      • Edelstein D.L.
      • Axilbund J.E.
      • Hylind L.M.
      • et al.
      Serrated polyposis: rapid and relentless development of colorectal neoplasia.
      ] found no association between SSLs and duodenal polyps in 2013.
      Little is known about the tumorigenesis of ampullary adenoma. It was postulated that adenoma of the papilla of Vater shared the same carcinogenic pathway with colon cancer, especially those in the right-side colon. However, ampullary carcinomas can be classified into two histological type, namely intestinal-type and pancreatobiliary-type [
      • Kimura W.
      • Ohtsubo K.
      Incidence, sites of origin, and immunohistochemical and histochemical characteristics of atypical epithelium and minute carcinoma of the papilla of Vater.
      ]. Similar to ampullary carcinomas, adenoma of the papilla of Vater can also be separated into the two types. Schönleben et al. [
      • Schonleben F.
      • Qiu W.
      • Allendorf J.D.
      • et al.
      Molecular analysis of PIK3CA, BRAF, and RAS oncogenes in periampullary and ampullary adenomas and carcinomas.
      ] analyzed mutation status of PIK3CA, BRAF, and RAS oncogenes in 24 ampullary tumors, 5 periampullary tumors, and 6 involving both in 2009, and found that BRAF mutation was more frequent in periampullary than ampullary neoplasia, which indicated that ampullary tumor went through the traditional colorectal adenoma-carcinoma sequence. Another two studies [
      • Ruemmele P.
      • Dietmaier W.
      • Terracciano L.
      • et al.
      Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions.
      ,
      • Agaram N.P.
      • Shia J.
      • Tang L.H.
      • et al.
      DNA mismatch repair deficiency in ampullary carcinoma: a morphologic and immunohistochemical study of 54 cases.
      further evaluated DNA mismatch repair (MMR) status of ampullary tumors. Then, MSI phenotype was found to be an early event in ampullary neoplasia and was reliably detected in precursor lesions, which pointed out that ampullary tumors also went through the MMR molecular pathway of carcinogenesis, similar to traditional colorectal cancer. In 2016, Shinichiet al. [
      • Yachida S.
      • Wood L.D.
      • Suzuki M.
      • et al.
      Genomic sequencing identifies ELF3 as a driver of ampullary carcinoma.
      ] conducted WES of 172 patients with ampullary carcinoma and revealed that the significantly mutated genes were TP53, KRAS, APC, CTNNB1, ACVR2A, ELF3, SMAD4, BRAF and so on in intestinal type, while KRAS, TP53, SMAD4, CDKN2A, CTNNB1, ELF3, ERBB3, GNAS, CDH10 were signicantly mutated in pancreatobiliary-type. Our sequenced case was an intestinal-type adenoma and we also identified somatic CTNNB1 and BRAF mutations, but no APC or KRAS mutation, which can be explained by the early stage of this adenoma. Besides, both lesions shared somatic ABCB1 mutations. ABCB1 is a member of the superfamily of ATP-binding cassette (ABC) transporters, involved in multidrug resistance [
      • Engle K.
      • Kumar G.
      Cancer multidrug-resistance reversal by ABCB1 inhibition: a recent update.
      ]. Andersen et al. [
      • Andersen V.
      • Vogel U.
      • Godiksen S.
      • et al.
      Low ABCB1 gene expression is an early event in colorectal carcinogenesis.
      ] confirmed that ABCB1 mRNA levels were highest in normal tissue and significantly lower in mild/moderate and severe dysplasia, as well as CRC tissue, suggesting low ABCB1 expression is an early event in colorectal tumorigenesis.

      5. Conclusions

      In summary, there was a significant association between ampullary tumors and colorectal polyps of all histology as well as advanced colorectal adenoma observed in this study. We also preliminarily confirmed ABCB1 mutation might be an early event in the tumorigenesis of both ampulla and colon adenoma. The present study recommends routine colonoscopy in patients with sporadic ampullary tumors. Future larger-scale multi-center researches and exploration of the underlying mechanisms are warranted to provide a better understanding of ampullary epithelial tumors.

      Author contributions

      Chunyan Peng and Lei Wang designed the framework of the study; Fan Zhou, Ying Xie, Dehua Tang and Meng Zhang collected endoscopic, clinicopathological and follow-up data; Lu He reviewed all the slides; Fan Zhou and Lu He interpreted the data and edited the figures and tables; Ying Xie, Xiaoping Zou, Ying Lv and Guifang Xu contributed to the literature review; Fan Zhou wrote the manuscript; Lu He, Chunyan Peng, Lei Wang and Xiaoping Zou revised the manuscript. All the authors read and approved the final paper.

      Ethics approval and consent to participate

      This study was approved by the Ethics Committee of Nanjing Drum Tower Hospital, Nanjing University Medical School. All procedures in this study were conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from each patient involved in our research.

      Funding

      This work was supported by the Natural Science Foundation of Jiangsu Province ( BK20220178 ), and National Natural Science Foundation of China (Grant No. 62006113 ).

      Data availability statement

      The data used and/or analyzed during the current study are available from the corresponding author on a reasonable request.

      Declaration of Competing Interest

      No potential conflicts of interest were disclosed.

      Acknowledgments

      None.

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