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Clinical and Molecular Characteristics of Post-Colonoscopy Colorectal Cancer: A Population-based Study

      Background & Aims

      Colonoscopy provides incomplete protection from colorectal cancer (CRC), but determinants of post-colonoscopy CRC are not well understood. We compared clinical features and molecular characteristics of CRCs diagnosed at different time intervals after a previous colonoscopy.

      Methods

      We performed a population-based, cross-sectional study of incident CRC cases in Denmark (2007–2011), categorized as post-colonoscopy or detected during diagnostic colonoscopy (in patients with no prior colonoscopy). We compared prevalence of proximal location and DNA mismatch repair deficiency (dMMR) in CRC tumors, relative to time since previous colonoscopy, using logistic regression and cubic splines to assess temporal variation.

      Results

      Of 10,365 incident CRCs, 725 occurred after colonoscopy examinations (7.0%). These were more often located in the proximal colon (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.90–2.89) and were more likely to have dMMR (OR, 1.26; 95% CI, 1.00–1.59), but were less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48–0.89) compared with CRCs diagnosed in patients with no prior colonoscopy. The highest proportions of proximal and/or dMMR tumors were observed in CRCs diagnosed 3–6 years after colonoscopy, but these features were still more frequent among cancers diagnosed up to 10 years after colonoscopy. The relative excess of dMMR tumors was most pronounced in distal cancers. In an analysis of 85 cases detected after colonoscopy, we found BRAF mutations in 23% of tumors and that 7% of cases had features of Lynch syndrome. Colonoscopy exams were incomplete in a higher proportion of cases diagnosed within <1 year (in 38%) than in those diagnosed within 1–10 years after colonoscopy (16%).

      Conclusions

      In a study of incident CRC cases in Denmark, we observed that tumors found in patients who have undergone colonoscopy are more often proximal and have dMMR compared to CRCs detected in patients without previous colonoscopies. The excess of right-sided tumors and the modest independent effects of dMMR reinforce the importance of proper colonoscopic examination of the proximal large bowel.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), CRC (colorectal cancer), DCR (Danish Cancer Registry), dMMR (mismatch repair deficiency), IHC (immunohistochemistry), OR (odds ratio)
      See Covering the Cover synopsis on page 777; see editorial on page 793.
      Colonoscopy with polypectomy reduces risk of subsequent colorectal cancer (CRC), and a negative examination portends a reduced risk as well.
      • Brenner H.
      • Haug U.
      • Arndt V.
      • et al.
      Low risk of colorectal cancer and advanced adenomas more than 10 years after negative colonoscopy.
      • Winawer S.J.
      • Zauber A.G.
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      • et al.
      Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup.
      However, CRC diagnoses after a negative or clearing colonoscopy suggest that the protective effect of colonoscopy is weaker than originally estimated.
      • Brenner H.
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      • et al.
      Protection from colorectal cancer after colonoscopy: a population-based, case-control study.
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      A pooled analysis of advanced colorectal neoplasia diagnoses after colonoscopic polypectomy.
      • Sawhney M.S.
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      • Gudiseva S.
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      Microsatellite instability in interval colon cancers.
      • Kaminski M.F.
      • Regula J.
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      Quality indicators for colonoscopy and the risk of interval cancer.
      • Cooper G.S.
      • Xu F.
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      • et al.
      Prevalence and predictors of interval colorectal cancers in medicare beneficiaries.
      • Singh H.
      • Nugent Z.
      • Demers A.A.
      • et al.
      Rate and predictors of early/missed colorectal cancers after colonoscopy in Manitoba: a population-based study.
      Understanding how these cancers occur would inform interventions to optimize colonoscopy for CRC screening and prevention.
      Colonoscopy quality is clearly implicated in post-colonoscopy or “interval” CRC because risk has been associated with both endoscopist characteristics (eg, specialty training and adenoma detection rates)
      • Kaminski M.F.
      • Regula J.
      • Kraszewska E.
      • et al.
      Quality indicators for colonoscopy and the risk of interval cancer.
      • Corley D.A.
      • Jensen C.D.
      • Marks A.R.
      • et al.
      Adenoma detection rate and risk of colorectal cancer and death.
      and indicators of examination quality (eg, preparation quality and completeness of examination).
      • Brenner H.
      • Chang-Claude J.
      • Jansen L.
      • et al.
      Role of colonoscopy and polyp characteristics in colorectal cancer after colonoscopic polyp detection: a population-based case-control study.
      In addition, certain clinical characteristics have been found to be more common among post-colonoscopy CRCs, including older age at diagnosis, proximal tumor location, family history of CRC, and prior polypectomy.
      • Cooper G.S.
      • Xu F.
      • Barnholtz Sloan J.S.
      • et al.
      Prevalence and predictors of interval colorectal cancers in medicare beneficiaries.
      • Singh S.
      • Singh P.P.
      • Murad M.H.
      • et al.
      Prevalence, risk factors, and outcomes of interval colorectal cancers: a systematic review and meta-analysis.
      • Samadder N.J.
      • Curtin K.
      • Tuohy T.M.
      • et al.
      Characteristics of missed or interval colorectal cancer and patient survival: a population-based study.
      To date, only a few studies have investigated the molecular characteristics of post-colonoscopy tumors, finding a relatively high prevalence of DNA microsatellite instability,
      • Sawhney M.S.
      • Farrar W.D.
      • Gudiseva S.
      • et al.
      Microsatellite instability in interval colon cancers.
      • Nishihara R.
      • Wu K.
      • Lochhead P.
      • et al.
      Long-term colorectal-cancer incidence and mortality after lower endoscopy.
      • Richter J.M.
      • Pino M.S.
      • Austin T.R.
      • et al.
      Genetic mechanisms in interval colon cancers.
      CpG island methylator phenotypes,
      • Arain M.A.
      • Sawhney M.
      • Sheikh S.
      • et al.
      CIMP status of interval colon cancers: another piece to the puzzle.
      and somatic BRAF mutations.
      • Shaukat A.
      • Arain M.
      • Thaygarajan B.
      • et al.
      Is BRAF mutation associated with interval colorectal cancers?.
      Published data regarding molecular characteristics of post-colonoscopy CRC leave several questions unanswered because relevant studies were not population-based and included only limited numbers of cases (167 in total).
      • Sawhney M.S.
      • Farrar W.D.
      • Gudiseva S.
      • et al.
      Microsatellite instability in interval colon cancers.
      • Nishihara R.
      • Wu K.
      • Lochhead P.
      • et al.
      Long-term colorectal-cancer incidence and mortality after lower endoscopy.
      • Richter J.M.
      • Pino M.S.
      • Austin T.R.
      • et al.
      Genetic mechanisms in interval colon cancers.
      • Arain M.A.
      • Sawhney M.
      • Sheikh S.
      • et al.
      CIMP status of interval colon cancers: another piece to the puzzle.
      • Shaukat A.
      • Arain M.
      • Thaygarajan B.
      • et al.
      Is BRAF mutation associated with interval colorectal cancers?.
      To date, all investigations have examined CRCs diagnosed at arbitrary intervals (eg, 5 or 10 years) after colonoscopy, with little attention to possible interplay among molecular characteristics of post-colonoscopy cancers and clinical factors. The independent associations of each characteristic with risk of cancer at different time intervals after colonoscopy remain unclear.
      To examine the clinical and molecular features of post-colonoscopy CRC, we conducted a population-based study comparing clinical characteristics, tumor location, and mismatch repair deficiency (dMMR) between cases diagnosed at first colonoscopy and those diagnosed at different time intervals after a colonoscopy. We also conducted a detailed analysis of the molecular characteristics of a subset of post-colonoscopy CRC cases and the quality of the colonoscopy that preceded them.

      Methods

       Study Design

      Using Danish medical registries, we conducted a population-based nationwide study of all CRCs diagnosed during 2007–2011. We subsequently characterized subjects with incident CRC as “diagnostic colonoscopy only” if their only prior colonoscopic exam was within 180 days of CRC diagnosis, or post-colonoscopy if they had at least 1 prior colonoscopy >180 days before diagnosis. The latest colonoscopy performed >180 days before CRC diagnosis was defined as the “index” examination.

       Databases

      Each Danish resident is assigned a unique civil registration number, facilitating linkage of individual-level data among registries.
      • Frank L.
      Epidemiology. The epidemiologist's dream: Denmark.
      The Danish National Patient Registry has recorded all inpatient hospital encounters since 1977, as well as outpatient hospital encounters since 1995,
      • Lynge E.
      • Sandegaard J.L.
      • Rebolj M.
      The Danish National Patient Register.
      covering essentially all colonoscopy in the country.
      • Erichsen R.
      • Baron J.A.
      • Stoffel E.M.
      • et al.
      Characteristics and survival of interval and sporadic colorectal cancer patients: a nationwide population-based cohort study.
      The Danish Cancer Registry (DCR) records all incident cancers diagnosed nationwide, coded using the International Classification of Diseases, Tenth Revision, with diagnosis date, tumor location, and stage.
      • Gjerstorff M.L.
      The Danish Cancer Registry.
      The National Pathology Registry archives pathology results from all specimens examined since 1997, using International Systematized Nomenclature of Medicine codes.
      • Erichsen R.
      • Lash T.L.
      • Hamilton-Dutoit S.J.
      • et al.
      Existing data sources for clinical epidemiology: the Danish National Pathology Registry and Data Bank.

       Nationwide Incident Colorectal Cancer Cases

      We queried the DCR to identify all individuals newly diagnosed with CRC during the 5-year study period. Their records were linked to the Danish National Patient Registry to identify individuals who underwent 1 or more colonoscopies before their CRC diagnosis. We defined post-colonoscopy cases as those with 1 or more examinations >180 days before their CRC diagnosis in order to minimize contamination with diagnostic examinations, as individual chart reviews were not performed in the nationwide analysis.
      Data abstracted included demographic characteristics, tumor location (classified as proximal: cecum through transverse colon, distal: splenic flexure through rectum, or unspecified), CRC stage at diagnosis (classified as localized, regional, metastatic, or unknown), histopathologic features, history of inflammatory bowel disease, and tumor DNA MMR protein expression. Testing for dMMR has been performed routinely as part of the clinical histopathologic evaluation of CRC resection specimens since 2007, with results recorded in the Pathology Registry. Chart reviews conducted among the 19 Danish pathology institutes demonstrated that 12 had recorded dMMR status for >75% of CRC cases, whereas 7 recorded results less consistently (range, 0%–64% of cases). To minimize potential bias, we restricted our study population to CRC cases evaluated at the 12 institutes performing dMMR testing regularly, representing 69% of CRC cases nationwide (Figure 1). dMMR status in CRC was assessed on the basis of immunohistochemistry (IHC) for MMR proteins with MLH1 and MSH2 in all cases, and for MSH6 and PMS2 in 74% and 45% of cases, respectively. Tumors exhibiting absent expression of 1 or more MMR proteins were classified as having dMMR and therefore microsatellite instability.
      Figure thumbnail gr1
      Figure 1Flowchart of CRC cases diagnosed nationwide in Denmark during 2007–2011, showing post-colonoscopy (PC) vs diagnostic colonoscopy (DC) cases, and a hospital-based subsample of PC cases.

       Hospital-based Subset of Post-Colonoscopy Cases

      Using the DCR, we ascertained CRC cases diagnosed at Aalborg University Hospital, serving a population of approximately 640,000. We identified 101 candidate post-colonoscopy cases identified >90 days after colonoscopy, with available endoscopic records and formalin-fixed paraffin-embedded tumor blocks. Medical records were reviewed to confirm post-colonoscopy status. The latest colonoscopy performed >90 days before CRC diagnosis was defined as the “index” examination. After record reviews, 16 (16%) cases were excluded: the index exam was flexible sigmoidoscopy, not colonoscopy (n = 5); the CRC diagnosis was known at the time (or within 90 days) of the index colonoscopy (n = 7); or pathology review did not confirm colorectal adenocarcinoma (n = 4). Eighty-five post-colonoscopy CRC tumors remained for molecular analysis. Colonoscopy reports were abstracted to determine indication, bowel preparation quality, completeness of examination, findings including polyps (histology, number, and location), and polypectomy technique. Advanced adenomas were defined as those ≥10 mm in size, and/or with high-grade dysplasia or villous histology.
      An expert gastrointestinal pathologist (SRH) reviewed slides recut from the CRC tumor blocks without access to clinical information. For each tumor, nuclear expression of 4 MMR proteins (MLH1, MSH2, MSH6, and PMS2) was evaluated by IHC.
      • De Jesus-Monge W.E.
      • Gonzalez-Keelan C.
      • Zhao R.
      • et al.
      Mismatch repair protein expression and colorectal cancer in Hispanics from Puerto Rico.
      • Bartley A.N.
      • Luthra R.
      • Saraiya D.S.
      • et al.
      Identification of cancer patients with Lynch syndrome: clinically significant discordances and problems in tissue-based mismatch repair testing.
      DNA extracted from microdissected cancer tissue was evaluated for somatic mutations in BRAF (V600E), KRAS (codons 12, 13, 61, and 146), NRAS (codons 12,13), and PIK3CA (exons 9 and 20) using Sequenom MassARRAY methodology.
      • Greaves W.O.
      • Verma S.
      • Patel K.P.
      • et al.
      Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma.
      • Portier B.P.
      • Kanagal-Shamanna R.
      • Luthra R.
      • et al.
      Quantitative assessment of mutant allele burden in solid tumors by semiconductor-based next-generation sequencing.
      CRCs demonstrating absent nuclear expression of 1 or more MMR proteins were characterized as dMMR. Cases with equivocal IHC status were investigated using polymerase chain reaction amplification of a DNA microsatellite marker panel (BAT-25, BAT-26, BAT-40, TGFbRII, D2S123, D5S345, and D17S250).
      Comprehensive molecular characterization of human colon and rectal cancer.
      dMMR tumors were further characterized as “sporadic” or “Lynch syndrome” using current diagnostic algorithms.
      • Bellizzi A.M.
      • Frankel W.L.
      Colorectal cancer due to deficiency in DNA mismatch repair function: a review.
      Tumors with loss of MLH1 protein on IHC with BRAF gene mutation were classified as sporadic. Tumors with loss of MLH1 protein without BRAF mutation were studied further for MLH1 promoter hypermethylation using pyrosequencing.
      • Djordjevic B.
      • Barkoh B.A.
      • Luthra R.
      • et al.
      Relationship between PTEN, DNA mismatch repair, and tumor histotype in endometrial carcinoma: retained positive expression of PTEN preferentially identifies sporadic non-endometrioid carcinomas.
      Tumors with loss of MLH1 protein without BRAF mutation or MLH1 promoter hypermethylation, and those showing loss of both MSH2 and MSH6 proteins, or MSH6 or PMS2 proteins only, were classified as consistent with Lynch syndrome.

       Statistical Analysis

      In the nationwide analysis, we used standard descriptive statistics, t tests, and contingency table analyses to examine differences between clinical and molecular features of diagnostic colonoscopy and post-colonoscopy CRC cases diagnosed at various intervals after the index colonoscopy. For dichotomous risk factors, we used restricted cubic splines
      • Marrie R.A.
      • Dawson N.V.
      • Garland A.
      Quantile regression and restricted cubic splines are useful for exploring relationships between continuous variables.
      (knots at 1, 3, 6, 9, and 12 years) to assess variation in the post-colonoscopy to diagnostic prevalence ratio over time, adjusted for age at CRC diagnosis and sex (age only in analyses of sex). We visually estimated the duration of time that the post-colonoscopy to diagnostic differences persisted after the index colonoscopy, and the period during which they were greatest. Subsequently, we used logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the associations between patient and tumor characteristics and post-colonoscopy vs diagnostic status within the selected time periods after the index colonoscopy. As index colonoscopy exams were performed at >70 endoscopy centers, we grouped CRC cases into 12 study centers corresponding to the regional pathology institutes serving each center as a proxy to adjust for potential differences by hospital. Interactions were assessed using Wald tests. Models included age, sex, site of cancer (proximal vs distal), MMR status (deficient vs proficient), and stage (metastatic vs not metastatic), with adjustment for hospital. Goodness of fit for the logistic regression models was assessed using the Hosmer-Lemeshow test.
      To assess the impact of our definition of diagnostic CRC, we performed a sensitivity analysis extending the definition of diagnostic CRC cases to include those diagnosed within 90 days after the index colonoscopy.
      For post-colonoscopy cases from the hospital sample, we used descriptive statistics to characterize patient and index procedure factors and tumor molecular characteristics among CRC cases diagnosed <1 year, 1–10 years, and >10 years after their index colonoscopy. Proportions were compared with Fisher’s exact tests.
      Analyses were conducted using SAS statistical software (version 9.3; SAS Institute, Cary, North Carolina). This study was approved by the Danish Data Protection Agency (2011-41-5913), the Danish Ethics Board (M-20110163), and the Institutional Review Board of the University of Texas, MD Anderson Cancer Center.

      Results

       Analysis of Nationwide Sample

      In the national sample, 10,365 incident CRC cases were identified during the study period at the pathology institutes included in the study: 725 (7%) post-colonoscopy cases and 9640 (93%) diagnostic CRC cases (Table 1). Sixty-eight (9%) post-colonoscopy cases were diagnosed within the first year after the index colonoscopy, 373 (51%) in the first 5 years, 566 (78%) in the first 10 years, and 159 (22%) more than 10 years later. Post-colonoscopy cases were older than diagnostic CRC cases and included a higher proportion of individuals with inflammatory bowel disease (Table 1; P < .001). However, there were no substantial differences by sex. Post-colonoscopy tumors were more often proximal and more often diagnosed at localized stages (P < .001).
      Table 1Characteristics of Colorectal Cancer Cases Diagnosed Nationwide (2007–2011) According to Time From Index Colonoscopy to Diagnosis (n = 10,365)
      Data restricted to 10,365 cases evaluated at 12 Danish institutes performing IHC testing for MMR proteins on >75% of CRC tumors, 2007–2011.
      CharacteristicsDiagnostic colonoscopy CRCPost-colonoscopy CRC (n = 725) by interval from index colonoscopy to CRC diagnosis
      Only tumors diagnosed >180 days after index colonoscopy were included as post-colonoscopy cases. See Methods for details.
      <3 y<5 y<10 y≥10 y
      No. of cases9640243373566159
      Age at CRC diagnosis, y, mean ± SD69.8 ± 11.173.5 ± 10.773.2 ± 10.473.8 ± 10.373.3 ± 11.5
      Sex, n (%)
       Male5132 (53.2)131 (53.9)187 (50.1)261 (46.1)66 (41.5)
       Female4508 (46.8)112 (46.1)186 (49.9)305 (53.9)93 (58.5)
      Inflammatory bowel disease, n (%)56 (0.6)18 (7.4)31 (8.3)55 (9.7)16 (10.1)
      Tumor location,
      Unknown tumor location: diagnostic colonoscopy cases: 313 (3.2%); post-colonoscopy cases: 35 (4.8%).
      n (%)
       Proximal2948 (30.6)136 (56.0)200 (53.6)306 (54.1)80 (50.3)
       Distal6379 (66.2)89 (36.6)151 (40.5)233 (41.2)71 (44.7)
      Stage,
      Unknown stage: diagnostic colonoscopy cases: 1398 (14.5%); post-colonoscopy cases: 98 (13.5%).
      n (%)
       Localized3833 (39.8)104 (42.8)165 (44.2)253 (44.7)79 (49.7)
       Regional2995 (31.1)69 (28.4)106 (28.4)167 (29.5)45 (28.3)
       Metastatic1414 (14.7)29 (11.9)42 (11.3)62 (11.0)21 (13.2)
      MMR status,
      Not tested: diagnostic colonoscopy cases: 1303 (13.5%); post-colonoscopy cases: 97 (13.4%).
      n (%)
       Proficient6952 (72.1)150 (61.7)232 (62.2)341 (60.2)107 (67.3)
       Deficient (loss)1385 (14.4)59 (24.3)92 (24.7)150 (26.5)30 (18.9)
      Absent MLH11190 (12.3)54 (22.2)82 (22.0)135 (23.9)25 (15.7)
      Absent MSH2127 (1.3)7 (2.9)9 (2.4)11 (1.9)3 (1.9)
      Absent MSH6 only80 (0.8)02 (0.5)5 (0.9)3 (1.9)
      Absent PMS2 only20 (0.2)01 (0.3)1 (0.2)0
      a Data restricted to 10,365 cases evaluated at 12 Danish institutes performing IHC testing for MMR proteins on >75% of CRC tumors, 2007–2011.
      b Only tumors diagnosed >180 days after index colonoscopy were included as post-colonoscopy cases. See Methods for details.
      c Unknown tumor location: diagnostic colonoscopy cases: 313 (3.2%); post-colonoscopy cases: 35 (4.8%).
      d Unknown stage: diagnostic colonoscopy cases: 1398 (14.5%); post-colonoscopy cases: 98 (13.5%).
      e Not tested: diagnostic colonoscopy cases: 1303 (13.5%); post-colonoscopy cases: 97 (13.4%).
      Tumor MMR testing was available for 8965 (86%) CRC cases in the study population; 1565 (17%) were dMMR; of these, 1350 (86%) exhibited loss of MLH1 expression and 844 (5.4%) loss of MSH2, MSH6, or PMS2 proteins. The prevalence of dMMR tumors was higher among post-colonoscopy than diagnostic cases in all the follow-up periods studied, across all clinical sites (Table 1, Supplementary Figure 1). Including CRCs diagnosed >90 days (rather than >180 days) after the index colonoscopy in the post-colonoscopy case definition did not change these results (Supplementary Table 1).
      Compared with diagnostic cases, post-colonoscopy cancers were more often proximal and dMMR for up to 10 years after the index examination. The prevalence of these subtypes was highest among post-colonoscopy patients diagnosed 3–6 years after their index colonoscopies (Supplementary Figure 1).
      During the 3–6 years after the index colonoscopy, when post-colonoscopy and diagnostic cases differed most, post-colonoscopy tumors were more likely to be located in the proximal colon (OR, 1.92; 95% CI, 1.36–2.72) and to have evidence of dMMR (OR, 1.53; 95% CI, 1.06–2.23). Older age and earlier stage were also independently associated with post-colonoscopy tumor status (Table 2). After adjustment for age and sex, dMMR was not independently associated with post-colonoscopy status in the proximal colon (OR, 1.40; 95% CI, 0.91–2.14), but approached statistical significance among the small numbers of distal tumors (OR, 2.08; 95% CI, 1.01–4.26; P for interaction = .41) (Table 2). There were broadly similar findings for post-colonoscopy cases during the entire 10-year period during which the post-colonoscopy cases differed from the diagnostic cases (Table 2, Figure 2). Results were similar when using a more sensitive definition of post-colonoscopy cases diagnosed >90 days to 10 years after the index examination (data not shown).
      Table 2Multivariate Analysis of Factors Independently Associated With Post-Colonoscopy Colorectal Cancer Between 180 Days and 10 Years After Index Colonoscopy (n = 566 Post-Colonoscopy Cases)
      CharacteristicsPost-colonoscopy cases3 to 6 years, OR (95% CI)180 days to 10 years, OR (95% CI)
      3 to 6 years180 days to 10 years
      Age at CRC diagnosis, y, mean ± SD73.2 ± 9.973.8 ± 10.31.02 (1.01–1.04)1.03 (1.02–1.04)
      Female sex116 (59.8)305 (53.9)0.74 (0.54–1.02)0.91 (0.75–1.10)
      Proximal tumor location104 (53.6)306 (54.1)1.92 (1.36–2.72)2.33 (1.89–2.88)
      Metastatic at presentation21 (10.8)62 (11.0)0.68 (0.41–1.13)0.66 (0.48–0.90)
      Mismatch repair-deficient
       Overall55 (28.4)140 (24.7)1.53 (1.06–2.23)1.28 (1.02–1.62)
       Proximal46 (23.7)120 (21.2)1.40 (0.91–2.14)1.18 (0.91–1.54)
       Distal9 (4.6)20 (3.5)2.08 (1.01–4.26)1.85 (1.14–3.01)
      NOTE. Logistic regression modeling used to estimate ORs and 95% CI for post-colonoscopy cancer over specified time intervals, adjusting for age, age, sex, site of cancer (proximal vs distal), MMR status (deficient vs proficient), stage (metastatic vs not metastatic), and clinical center.
      Figure thumbnail gr2
      Figure 2Restricted cubic spline analyses showing variation in the post-colonoscopy (PC)/diagnostic colonoscopy (DC) prevalence ratio (PR) of patient and tumor characteristics over time since prior colonoscopy, adjusted for sex and age (PR = solid line, 95% CI = dashed lines). (A) PR of proximal tumor location, (B) PR of MMR. PR of MMR stratified by tumor location proximal (C) and distal (D). Splines have 5 knots at 1, 3, 6, 9, and 12 years. MMR, mismatch repair.

       Analysis of Hospital-Based Subset of Post-Colonoscopy Cases

      The 85 post-colonoscopy cases were similar to the nationwide post-colonoscopy cases in age, sex, cancer stage, tumor location, and time between index colonoscopy and CRC diagnosis (Supplementary Table 2). The most frequent indications for the index examinations were symptoms (49%), polyp follow-up (26%), and history of colitis (9%). Adenomas had been found in 27 (31%) subjects, including 26 with advanced adenomas. Overall, quality of bowel preparation was not reliably recorded; however, 18 (21%) post-colonoscopy cases had endoscopic reports from the index colonoscopy, which noted that the exam was incomplete (specifically that the cecum was not reached), and this was more common in cases diagnosed at shorter intervals: 38% among those diagnosed in the first year after the index colonoscopy and 16% among those diagnosed 1–10 years after (P = .07).
      Overall, 20 (24%) post-colonoscopy tumors exhibited dMMR. In tumors diagnosed within 10 years of the index examination, BRAF mutations were identified in 16 (19%) tumors (12 were dMMR), KRAS/NRAS mutations in 23 (27%), and PIK3CA mutations in 16 (19%). A total of 6 (7%) tumors had molecular characteristics of Lynch syndrome (Figure 3). All Lynch syndrome cancers occurred within the first 10 years after index colonoscopy. Four post-colonoscopy cases (5%) occurring <10 years after the index colonoscopy had synchronous primary CRCs, 3 of which exhibited dMMR with somatic BRAF mutations, which are features of the serrated pathway.
      • Rex D.K.
      • Ahnen D.J.
      • Baron J.A.
      • et al.
      Serrated lesions of the colorectum: review and recommendations from an expert panel.
      Figure thumbnail gr3
      Figure 3Distribution of molecular characteristics among hospital-based PC cases, by interval between colonoscopy and CRC diagnosis (n = 85). NOTE: Figures are not proportional between time intervals. Area exterior to microsatellite stable (MSS) circle represents microsatellite instability-high (MSI-Hi) tumors.

      Discussion

      In this large population-based study of >700 CRC cases diagnosed 180 days to 20+ years after colonoscopy, we found that proximal location and dMMR were overrepresented among post-colonoscopy cancers diagnosed up to 10 years later. The characteristics of post-colonoscopy cases varied over time, with the highest prevalence of proximal location and dMMR 3–6 years after the index colonoscopy. The relative excess of dMMR tumors was more pronounced among cancers located in the distal colon. The nationwide findings were confirmed in analyses of post-colonoscopy cancers diagnosed up to 10 years after colonoscopy at a single center. Of these, 24% were dMMR, with 7% exhibiting molecular features of Lynch syndrome.
      Our findings agree with previous research showing that CRCs diagnosed within 3 or 5 years after colonoscopy are more likely to be located in the proximal colon and exhibit dMMR than those diagnosed without a previous colonoscopy.
      • Sawhney M.S.
      • Farrar W.D.
      • Gudiseva S.
      • et al.
      Microsatellite instability in interval colon cancers.
      • Nishihara R.
      • Wu K.
      • Lochhead P.
      • et al.
      Long-term colorectal-cancer incidence and mortality after lower endoscopy.
      • Richter J.M.
      • Pino M.S.
      • Austin T.R.
      • et al.
      Genetic mechanisms in interval colon cancers.
      Although some studies have suggested that the risk of interval cancer may be higher for women than men,
      • Brenner H.
      • Chang-Claude J.
      • Seiler C.M.
      • et al.
      Interval cancers after negative colonoscopy: population-based case-control study.
      we found no sex differences during the overall 10-year follow-up period.
      Molecular characteristics of post-colonoscopy CRC have not been as well investigated as clinical features and this population-based study incorporates molecular phenotypes. Previous investigations of post-colonoscopy cases that reported molecular features included a total of 167 tumors diagnosed within 5 years of a colonoscopy (with a maximum cohort size of 63),
      • Sawhney M.S.
      • Farrar W.D.
      • Gudiseva S.
      • et al.
      Microsatellite instability in interval colon cancers.
      • Samadder N.J.
      • Curtin K.
      • Tuohy T.M.
      • et al.
      Characteristics of missed or interval colorectal cancer and patient survival: a population-based study.
      • Nishihara R.
      • Wu K.
      • Lochhead P.
      • et al.
      Long-term colorectal-cancer incidence and mortality after lower endoscopy.
      • Richter J.M.
      • Pino M.S.
      • Austin T.R.
      • et al.
      Genetic mechanisms in interval colon cancers.
      • Arain M.A.
      • Sawhney M.
      • Sheikh S.
      • et al.
      CIMP status of interval colon cancers: another piece to the puzzle.
      • Shaukat A.
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      • Thaygarajan B.
      • et al.
      Is BRAF mutation associated with interval colorectal cancers?.
      in contrast to 725 included in our analysis (566 diagnosed within 10 years). Our findings demonstrate once again that proximal tumors and dMMR tumors are overrepresented among post-colonoscopy CRC cases.
      • Sawhney M.S.
      • Farrar W.D.
      • Gudiseva S.
      • et al.
      Microsatellite instability in interval colon cancers.
      • Samadder N.J.
      • Curtin K.
      • Tuohy T.M.
      • et al.
      Characteristics of missed or interval colorectal cancer and patient survival: a population-based study.
      • Nishihara R.
      • Wu K.
      • Lochhead P.
      • et al.
      Long-term colorectal-cancer incidence and mortality after lower endoscopy.
      • Brenner H.
      • Chang-Claude J.
      • Seiler C.M.
      • et al.
      Interval cancers after negative colonoscopy: population-based case-control study.
      Our large sample size allowed use of multivariable analyses to estimate the independent effects of tumor location and molecular characteristics. Proximal location and dMMR commonly occur together in sporadic CRC, and we were able to demonstrate that although the association of proximal location with post-colonoscopy CRC is clear, the independent effect of dMMR is mostly exhibited in the distal colorectum.
      Our analysis of the 85 hospital-based post-colonoscopy cases provided an opportunity to examine colonoscopy quality and molecular characteristics of tumors in more detail. Our finding of incomplete index examinations in 38% of post-colonoscopy cases diagnosed within the first year after a colonoscopy suggests that exam quality is important, especially in diagnoses made soon after colonoscopy. While the majority of sporadic as well as post-colonoscopy tumors develop through the chromosomal instability pathway, our molecular analyses confirmed that dMMR tumors are overrepresented among post-colonoscopy CRCs. Lynch syndrome–associated neoplasms arise through this mutator pathway and are known to progress rapidly to cancer (often within 3 years after colonoscopy).
      • Engel C.
      • Rahner N.
      • Schulmann K.
      • et al.
      Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer.
      • Jarvinen H.J.
      • Renkonen-Sinisalo L.
      • Aktan-Collan K.
      • et al.
      Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members.
      Interestingly, we did find that the prevalence of Lynch syndrome among post-colonoscopy cases (7%) was more than double the reported population prevalence of 2%–3%,
      • Ladabaum U.
      • Ford J.M.
      • Martel M.
      • et al.
      American Gastroenterological Association technical review on the diagnosis and management of Lynch syndrome.
      and these tumors represented one-third of dMMR cases within 10 years of a prior colonoscopy. We also found that 1 in 5 post-colonoscopy cases were BRAF-mutated, a feature of serrated pathway carcinogenesis.
      • Rex D.K.
      • Ahnen D.J.
      • Baron J.A.
      • et al.
      Serrated lesions of the colorectum: review and recommendations from an expert panel.
      However, the lack of controls in this analysis makes these findings difficult to interpret.
      A novel feature of our analysis is that we included post-colonoscopy CRCs diagnosed during a wide range of time intervals after index colonoscopy and found considerable heterogeneity in the proportions of post-colonoscopy cancers that were proximal and dMMR, depending on time since the index examination. Other strengths of this study include the large population-based sample with availability of data regarding MMR status. Our detailed review of medical records and tumors of a representative subset of post-colonoscopy cancers corroborates the nationwide findings.
      However, we acknowledge that our study has certain limitations. Quality of colonoscopy exams is a determinant of effectiveness in preventing CRC, and is impacted by the success of the patient’s bowel cleanout as well as the expertise of the endoscopist. While 80% of colonoscopies in Denmark are performed by gastrointestinal specialists,
      • Andersen F.H.
      detailed data regarding endoscopist and procedure characteristics (eg, adenoma detection rate, withdrawal time, cleanliness) were not available for the nationwide cases and thus the quality of individual index colonoscopy exams could not be assessed. A number of reviews of outcomes of CRC screening exams performed in Denmark have reported 89%–93% of colonoscopies are “complete,”
      • Andersen F.H.
      • Rolighed L.A.L.M.

      Dansk tarmkræftscreeningsdatabase Årsrapport 2014 Første 10 måneder 1. nationale screeningsrunde. Available at: https://www.sundhed.dk/content/cms/45/61245_dts%C3%A5rsrapport-2014_8-1-16_final_inklbilag.pdf2016. Accessed January 8, 2016.

      which is slightly below the quality benchmark of 95% cecal intubation rate, and lower than that reported in a European randomized clinical trial.
      • Bretthauer M.
      • Kaminski M.F.
      • Loberg M.
      • et al.
      Population-based colonoscopy screening for colorectal cancer: a randomized clinical trial.
      It is also worth noting that because colonoscopic screening for average-risk individuals was not current practice in Denmark during the study period, most individuals who underwent colonoscopies had symptoms or previous polyps that prompted colonoscopic evaluation. Consequently, it is possible our findings may not be generalizable to populations in which high-quality colonoscopy screening of asymptomatic average-risk individuals is more widely employed. We recognize that our analysis depends on the accuracy of our data. While the DCR offers near-complete ascertainment of cancer cases, it is possible that post-colonoscopy and diagnostic CRC cases may have been misclassified, as occurred in 15% of post-colonoscopy cases reviewed in our hospital sample (10% in the national sample with the 180-day time window).
      Our finding that 7% of CRC cases in Denmark occurred in individuals who had undergone a prior colonoscopy is a clinical and medicolegal concern. Our data imply that the problem of post-colonoscopy cancers, though greatest about 3–6 years after colonoscopy, persists to some extent far longer than the 5-year time frame commonly used to define so-called “interval” cancers. The high proportion of proximal tumors, in conjunction with the frequency of incomplete colonoscopy among post-colonoscopy cases diagnosed within the first year after colonoscopy, supports the popular assumption that many cancers diagnosed soon after colonoscopy result from missed lesions.
      • Andersen F.H.
      • Rex D.K.
      Avoiding and defending malpractice suits for postcolonoscopy cancer: advice from an expert witness.
      However, the heterogeneity in clinical and molecular features of cancers diagnosed at different time intervals suggests post-colonoscopy CRCs are likely multifactorial in their etiology and clinical behavior. Studies consistently show that colonoscopy affords less protection against proximal cancers
      • Brenner H.
      • Chang-Claude J.
      • Seiler C.M.
      • et al.
      Protection from colorectal cancer after colonoscopy: a population-based, case-control study.
      • Cooper G.S.
      • Xu F.
      • Barnholtz Sloan J.S.
      • et al.
      Prevalence and predictors of interval colorectal cancers in medicare beneficiaries.
      • Baxter N.N.
      • Goldwasser M.A.
      • Paszat L.F.
      • et al.
      Association of colonoscopy and death from colorectal cancer.
      • le Clercq C.M.
      • Bouwens M.W.
      • Rondagh E.J.
      • et al.
      Postcolonoscopy colorectal cancers are preventable: a population-based study.
      and dMMR tumors are more frequent among proximal cancers. The proximal and distal colon differ with respect to embryologic origin and gene expression profiles, prompting some to suggest that these might be considered as 2 distinct organs.
      • Carethers J.M.
      One colon lumen but two organs.
      Whether the precursors of post-colonoscopy CRCs are simply harder to detect and/or resect endoscopically, or whether their behavior differs on the basis of anatomic location and/or molecular subtype remains unclear and warrants further investigation. Our study adds to the literature supporting that a paramount concern is effective visualization of the proximal large bowel to maximize the effectiveness of colonoscopy.

      Acknowledgments

      The authors appreciate the technical assistance provided by Dr Raja Luthra and Trupti Methta for the laboratory work performed at MD Anderson.

      Supplementary Material

      Figure thumbnail fx1
      Supplementary Figure 1Prevalence of proximal tumor location (A) and dMMR (B) among post-colonoscopy CRC cases (n = 628 cases with IHC results), stratified by sex. Blue, female; red, male. Dashed lines indicate prevalence of either factor among diagnostic colonoscopy cases for 3926 females and 4340 males; error bars indicate 95%.
      Supplementary Table 1Sensitivity Analysis: Characteristics of Colorectal Cancer Cases Diagnosed Nationwide (2007–2011) According to Time From Index Colonoscopy to Colorectal Cancer Diagnosis, Defining Post-Colonoscopy as >90 Days Post-Index Colonoscopy (n = 10,365)
      Data restricted to 10,365 cases evaluated at 12 Danish institutes performing IHC testing for MMR proteins on >75% of CRC tumors 2007–2011.
      CharacteristicsDiagnostic colonoscopy CRCPost-colonoscopy CRC interval
      Only tumors diagnosed >3 months of prior colonoscopy were considered post-colonoscopy cases. See Methods for details.
      <3 y<5 y<10 y≥10 y+
      No. of cases9552331461654159
      Age at CRC diagnosis, y, mean ± SD69.8 ± 11.173.3 ± 10.673.2 ± 10.473.7 ± 10.473.3 ± 11.5
      Sex, n (%)
       Male5087 (53.3)176 (53.2)232 (50.3)306 (46.8)66 (41.5)
       Female4465 (46.7)155 (46.8)229 (49.7)348 (53.2)93 (58.5)
      Inflammatory bowel disease, n (%)52 (0.54)22 (6.6)35 (7.6)59 (9.0)16 (10.1)
      Tumor location,
      Unknown tumor location: diagnostic colonoscopy cases: 310 (3.2%); post-colonoscopy cases: 38 (4.7%).
      n (%)
       Proximal2905 (30.4)179 (54.1)243 (52.7)349 (53.4)80 (50.3)
       Distal6337 (66.3)131 (39.6)193 (41.9)275 (42.0)71 (44.7)
      Stage,
      Unknown stage: diagnostic colonoscopy cases: 1382 (14.5%); post-colonoscopy cases: 114 (14.0%).
      n (%)
       Localized3797 (39.8)140 (42.3)201 (43.6)289 (44.2)79 (49.7)
       Regional2970 (31.1)94 (28.4)131 (28.4)192 (29.4)45 (28.3)
       Metastatic1403 (14.7)40 (12.1)53 (11.5)73 (11.2)21 (13.2)
      MMR status,
      Not tested: diagnostic colonoscopy cases: 1286 (13.5%); post-colonoscopy cases: 114 (14.0%).
      n (%)
       Proficient6897 (72.2)205 (61.9)287 (62.3)396 (60.6)107 (67.3)
       Deficient (loss)1369 (14.3)75 (22.7)108 (23.4)166 (25.4)30 (18.9)
      Absent MLH11175 (12.3)69 (20.8)97 (21.0)150 (22.9)25 (15.7)
      Absent MSH2126 (1.3)8 (2.4)10 (2.2)12 (1.8)3 (1.9)
      a Data restricted to 10,365 cases evaluated at 12 Danish institutes performing IHC testing for MMR proteins on >75% of CRC tumors 2007–2011.
      b Only tumors diagnosed >3 months of prior colonoscopy were considered post-colonoscopy cases. See Methods for details.
      c Unknown tumor location: diagnostic colonoscopy cases: 310 (3.2%); post-colonoscopy cases: 38 (4.7%).
      d Unknown stage: diagnostic colonoscopy cases: 1382 (14.5%); post-colonoscopy cases: 114 (14.0%).
      e Not tested: diagnostic colonoscopy cases: 1286 (13.5%); post-colonoscopy cases: 114 (14.0%).
      Supplementary Table 2Endoscopic and Tumor Characteristics of Post-Colonoscopy Colorectal Cancer Cases, by Time From Index Colonoscopy to Colorectal Cancer Diagnosis, Aalborg Hospital, 2000–2009 (n = 85)
      CharacteristicsTotalInterval <1 yearInterval 1–10 yearsInterval >10 years
      No. of cases85165811
      Age at diagnosis, y, mean (range)72 (37–91)70 (42–86)71 (37–90)81 (68–91)
      Sex, n (%)
       Male35 (41.2)9 (56.3)22 (37.9)4 (36.4)
       Female50 (58.8)7 (43.8)36 (62.1)7 (63.6)
      Indication for index colonoscopy, n (%)
       Symptom42 (49.4)13 (81.3)23 (39.7)6 (54.6)
       Follow-up of polyps22 (25.9)2 (12.5)17 (29.3)3 (27.3)
       History of colitis/IBD8 (9.4)1 (6.3)6 (10.3)1 (9.1)
       Family history of CRC5 (5.9)0 (0.0)5 (8.6)0 (0.0)
       Other/unknown8 (9.4)0 (0.0)7 (12.1)1 (9.1)
      Complete examination, n (%)
       Yes67 (78.8)10 (62.5)49 (84.5)8 (72.7)
       No18 (21.2)6 (37.5)9 (15.5)3 (27.3)
      Index examination findings, n (%)
       No adenoma58 (84.5)8 (50.0)41 (60.6)9 (81.8)
       Any adenoma27 (31.8)8 (50.0)17 (29.3)2 (18.2)
       Advanced adenoma26 (30.6)7 (43.8)17 (29.3)2 (18.2)
      CRC tumor size, cm, mean5.36.95.05.1
      Tumor location, n (%)
       Cecum/ascending37 (43.5)6 (37.5)24 (41.4)7 (63.6)
       Transverse3 (3.5)0 (0.0)3 (5.2)0 (0.0)
       Descending/sigmoid20 (23.5)6 (37.5)13 (22.4)1 (9.1)
       Rectal24 (28.2)4 (25.0)17 (29.3)3 (27.3)
       Unknown/missing1 (1.2)0 (0.0)1 (1.7)0 (0.0)
      Stage, n (%)
       Localized47 (55.2)9 (56.3)30 (51.7)8 (72.7)
       Regional24 (28.2)4 (25.0)18 (31.0)2 (18.2)
       Metastatic10 (11.8)3 (18.8)6 (10.3)1 (9.1)
       Unknown4 (4.7)0 (0.0)4 (6.9)0 (0.0)
      Molecular subtype, n (%)
       BRAF mutation20 (23.5)2 (12.5)14 (24.1)4 (36.4)
       KRAS mutation24 (28.2)7 (43.8)11 (19.0)6 (54.5)
       NRAS mutation6 (7.1)1 (6.3)4 (6.9)1 (9.1)
       PIK3CA mutation17 (20.0)4 (25.0)12 (20.7)1 (9.1)
       MMR proficient65 (76.5)14 (87.5)42 (72.4)9 (81.8)
       MMR deficient20 (23.5)2 (12.5)16 (27.6)2 (18.2)
      Lynch syndrome,
      MMR-deficient with MSH2 loss, MSH6 loss only, or MLH1 loss with BRAF wild-type and absent MLH1 methylation.
      n (%)
      6 (7.1)0 (0.0)6 (10.3)0 (0.0)
      IBD, inflammatory bowel disease.
      a MMR-deficient with MSH2 loss, MSH6 loss only, or MLH1 loss with BRAF wild-type and absent MLH1 methylation.

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