No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies

      Background & Aims

      Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1–2-year intervals), and Finland (patients evaluated at 2–3-year intervals).


      We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy).


      The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy.


      We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1–2-year intervals, and Finland, with 2–3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.

      Graphical abstract


      Abbreviations used in this paper:

      CI (confidence interval), CRC (colorectal cancer), HNPCC (hereditary nonpolyposis colorectal cancer), LS (Lynch syndrome), MMR (mismatch repair), UICC (International Union Against Cancer)
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        • Lynch H.T.
        • de la Chapelle A.
        Hereditary colorectal cancer.
        N Engl J Med. 2003; 348: 919-932
        • Moller P.
        • Seppala T.
        • Bernstein I.
        • et al.
        Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.
        Gut. 2017; 66: 464-472
        • Engel C.
        • Loeffler M.
        • Steinke V.
        • et al.
        Risks of less common cancers in proven mutation carriers with lynch syndrome.
        J Clin Oncol. 2012; 30: 4409-4415
        • Win A.K.
        • Jenkins M.A.
        • Dowty J.G.
        • et al.
        Prevalence and penetrance of major genes and polygenes for colorectal cancer.
        Cancer Epidemiol Biomarkers Prev. 2017; 26: 404-412
        • Vasen H.F.
        • Mecklin J.P.
        • Khan P.M.
        • et al.
        The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).
        Dis Colon Rectum. 1991; 34: 424-425
        • Jarvinen H.J.
        • Aarnio M.
        • Mustonen H.
        • et al.
        Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer.
        Gastroenterology. 2000; 118: 829-834
        • de Jong A.E.
        • Hendriks Y.M.
        • Kleibeuker J.H.
        • et al.
        Decrease in mortality in Lynch syndrome families because of surveillance.
        Gastroenterology. 2006; 130: 665-671
        • Barrow P.
        • Khan M.
        • Lalloo F.
        • et al.
        Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome.
        Br J Surg. 2013; 100: 1719-1731
        • Engel C.
        • Rahner N.
        • Schulmann K.
        • et al.
        Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer.
        Clin Gastroenterol Hepatol. 2010; 8: 174-182
        • Vasen H.F.
        • Abdirahman M.
        • Brohet R.
        • et al.
        One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome.
        Gastroenterology. 2010; 138: 2300-2306
        • Tchetgen Tchetgen E.J.
        • Walter S.
        • Vansteelandt S.
        • et al.
        Instrumental variable estimation in a survival context.
        Epidemiology. 2015; 26: 402-410
        • Zauber A.G.
        • Winawer S.J.
        • O'Brien M.J.
        • et al.
        Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths.
        N Engl J Med. 2012; 366: 687-696
        • Jass J.R.
        • Stewart S.M.
        Evolution of hereditary non-polyposis colorectal cancer.
        Gut. 1992; 33: 783-786
        • De Jong A.E.
        • Morreau H.
        • Van Puijenbroek M.
        • et al.
        The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC.
        Gastroenterology. 2004; 126: 42-48
        • Mecklin J.P.
        • Sipponen P.
        • Jarvinen H.J.
        Histopathology of colorectal carcinomas and adenomas in cancer family syndrome.
        Dis Colon Rectum. 1986; 29: 849-853
        • Rijcken F.E.
        • Hollema H.
        • Kleibeuker J.H.
        Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation.
        Gut. 2002; 50: 382-386
        • Muller A.
        • Beckmann C.
        • Westphal G.
        • et al.
        Prevalence of the mismatch-repair-deficient phenotype in colonic adenomas arising in HNPCC patients: results of a 5-year follow-up study.
        Int J Colorectal Dis. 2006; 21: 632-641
        • Tanaka M.
        • Nakajima T.
        • Sugano K.
        • et al.
        Mismatch repair deficiency in Lynch syndrome-associated colorectal adenomas is more prevalent in older patients.
        Histopathology. 2016; 69: 322-328
        • Lynch H.T.
        • Smyrk T.C.
        • Watson P.
        • et al.
        Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review.
        Gastroenterology. 1993; 104: 1535-1549
        • Vasen H.F.
        • Nagengast F.M.
        • Khan P.M.
        Interval cancers in hereditary non-polyposis colorectal cancer (Lynch syndrome).
        Lancet. 1995; 345: 1183-1184
        • Lanspa S.J.
        • Jenkins J.X.
        • Cavalieri R.J.
        • et al.
        Surveillance in Lynch syndrome: how aggressive?.
        Am J Gastroenterol. 1994; 89: 1978-1980
        • Jass J.R.
        • Stewart S.M.
        • Stewart J.
        • et al.
        Hereditary non-polyposis colorectal cancer—morphologies, genes and mutations.
        Mutat Res. 1994; 310: 125-133
        • Edelstein D.L.
        • Axilbund J.
        • Baxter M.
        • et al.
        Rapid development of colorectal neoplasia in patients with Lynch syndrome.
        Clin Gastroenterol Hepatol. 2011; 9: 340-343
        • Ahadova A.
        • von Knebel Doeberitz M.
        • Blaker H.
        • et al.
        CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome.
        Fam Cancer. 2016; 15: 579-586
        • Kloor M.
        • Huth C.
        • Voigt A.Y.
        • et al.
        Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study.
        Lancet Oncol. 2012; 13: 598-606
        • Sekine S.
        • Mori T.
        • Ogawa R.
        • et al.
        Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis.
        Mod Pathol. 2017; 30: 1144-1151
        • Seppala T.
        • Pylvanainen K.
        • Evans D.G.
        • et al.
        Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.
        Hered Cancer Clin Pract. 2017; 15: 18
        • Sankila R.
        • Aaltonen L.A.
        • Jarvinen H.J.
        • et al.
        Better survival rates in patients with MLH1-associated hereditary colorectal cancer.
        Gastroenterology. 1996; 110: 682-687
        • Kloor M.
        • Michel S.
        • von Knebel Doeberitz M.
        Immune evasion of microsatellite unstable colorectal cancers.
        Int J Cancer. 2010; 127: 1001-1010
        • Boland C.R.
        Recent discoveries in the molecular genetics of Lynch syndrome.
        Fam Cancer. 2016; 15: 395-403
        • Parry S.
        • Win A.K.
        • Parry B.
        • et al.
        Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery.
        Gut. 2011; 60: 950-957
        • Moller P.
        • Seppala T.
        • Bernstein I.
        • et al.
        Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database.
        Gut. 2017; 66: 1657-1664
        • Plaschke J.
        • Engel C.
        • Kruger S.
        • et al.
        Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.
        J Clin Oncol. 2004; 22: 4486-4494
        • Rondagh E.J.
        • Gulikers S.
        • Gomez-Garcia E.B.
        • et al.
        Nonpolypoid colorectal neoplasms: a challenge in endoscopic surveillance of patients with Lynch syndrome.
        Endoscopy. 2013; 45: 257-264
        • Rahmi G.
        • Lecomte T.
        • Malka D.
        • et al.
        Impact of chromoscopy on adenoma detection in patients with Lynch syndrome: a prospective, multicenter, blinded, tandem colonoscopy study.
        Am J Gastroenterol. 2015; 110: 288-298
        • Boonstra J.J.
        • de Vos Tot Nederveen Cappel W.H.
        • Langers A.M.
        • et al.
        Colonoscopy in Lynch syndrome: the need for a new quality score.
        Fam Cancer. 2017; 16: 239-241