. 2019 Feb 28:17:8.

doi: 10.1186/s13053-019-0106-8. eCollection 2019.

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report

Toni T Seppälä^{1

2}, Aysel Ahadova³, Mev Dominguez-Valentin^{4

5}, Finlay Macrae^{6

7}, D Gareth Evans⁸, Christina Therkildsen⁹, Julian Sampson¹⁰, Rodney Scott¹¹, John Burn¹², Gabriela Möslein¹³, Inge Bernstein¹⁴, Elke Holinski-Feder^{15

16}, Kirsi Pylvänäinen¹⁷, Laura Renkonen-Sinisalo¹, Anna Lepistö¹, Charlotte Kvist Lautrup¹⁸, Annika Lindblom¹⁹, John-Paul Plazzer⁶, Ingrid Winship^{6

7}, Douglas Tjandra⁶, Lior H Katz²⁰, Stefan Aretz²¹, Robert Hüneburg^{22

23}, Stefanie Holzapfel^{22

23}, Karl Heinimann²⁴, Adriana Della Valle²⁵, Florencia Neffa²⁵, Nathan Gluck²⁶, Wouter H de Vos Tot Nederveen Cappel²⁷, Hans Vasen²⁸, Monika Morak^{15

16}, Verena Steinke-Lange^{15

16}, Christoph Engel²⁹, Nils Rahner³⁰, Wolff Schmiegel³¹, Deepak Vangala³¹, Huw Thomas³², Kate Green⁸, Fiona Lalloo⁸, Emma J Crosbie³³, James Hill⁸, Gabriel Capella^{34

35}, Marta Pineda^{34

35}, Matilde Navarro^{34

35}, Ignacio Blanco^{34

35}, Sanne Ten Broeke³⁶, Maartje Nielsen³⁷, Ken Ljungmann³⁸, Sigve Nakken⁴, Noralane Lindor³⁹, Ian Frayling¹⁰, Eivind Hovig^{4

40}, Lone Sunde⁴¹, Matthias Kloor³, Jukka-Pekka Mecklin^{42

43}, Mette Kalager^{4

44

45}, Pål Møller^{4

13

5}

Affiliations

¹ 1Department of Surgery, Helsinki University Central Hospital, P.O. Box 340, 00029 HUS Helsinki, Finland.
² 2University of Helsinki, Helsinki, Finland.
³ 3Heidelberg University Hospital and DKFZ, Heidelberg, Germany.
⁴ 4Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Olso, Norway.
⁵ 5Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
⁶ 6The Royal Melbourne Hospital, Melbourne, Australia.
⁷ 7University of Melbourne, Melbourne, Australia.
⁸ 8University of Manchester & Manchester University Hospitals Foundation Trust, Manchester, UK.
⁹ The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
¹⁰ 10Medical Genetics, Cardiff University, Cardiff, UK.
¹¹ University of Newcastle and the Hunter Medical Research Institute, Callaghan, Australia.
¹² 12University of Newcastle, Newcastle upon Tyne, UK.
¹³ 13University Witten-Herdecke, Wuppertal, Germany.
¹⁴ 14Dept. of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
¹⁵ 15Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
¹⁶ 16MGZ- Medical Genetics Center, Munich, Germany.
¹⁷ 17Central Finland Central Hospital, Education and Research, Jyväskylä, Finland.
¹⁸ 18Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
¹⁹ 19Karolinska Institutet, Stockholm, Sweden.
²⁰ 20Hadassah Medical Center, Jerusalem, and Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
²¹ 21Institute of Human Genetics, University of Bonn, Bonn, Germany.
²² 22Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
²³ 23Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
²⁴ 24Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²⁵ Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay.
²⁶ Tel-Aviv Soursky Medical Center, Tel-Aviv, Israel.
²⁷ 27Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands.
²⁸ 28Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
²⁹ 29Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
³⁰ 30Medical School, Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany.
³¹ 31Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
³² 32St Mark's Hospital, Department of Surgery and Cancer, Imperial College London, London, UK.
³³ 33University of Manchester and St Mary's Hospital, Manchester, UK.
³⁴ Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L'Hospitalet de Llobregat, Barcelona, Spain.
³⁵ Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
³⁶ 36University Medical Center Groningen, Groningen, the Netherlands.
³⁷ 37Leids Universitair Medisch Centrum, Leiden, Netherlands.
³⁸ 38Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
³⁹ 39Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ USA.
⁴⁰ 40Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
⁴¹ 41Department of Medical Genetics, Aarhus University Hospital, Aarhus, Denmark.
⁴² 42Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.
⁴³ 43Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
⁴⁴ 44University of Oslo, Oslo, Norway.
⁴⁵ 45Harvard School of Public Health, Boston, MA USA.

PMID: 30858900
PMCID: PMC6394091
DOI: 10.1186/s13053-019-0106-8

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report

Toni T Seppälä et al. Hered Cancer Clin Pract. 2019.

. 2019 Feb 28:17:8.

doi: 10.1186/s13053-019-0106-8. eCollection 2019.

Authors

Affiliations

¹ 1Department of Surgery, Helsinki University Central Hospital, P.O. Box 340, 00029 HUS Helsinki, Finland.
² 2University of Helsinki, Helsinki, Finland.
³ 3Heidelberg University Hospital and DKFZ, Heidelberg, Germany.
⁴ 4Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Olso, Norway.
⁵ 5Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
⁶ 6The Royal Melbourne Hospital, Melbourne, Australia.
⁷ 7University of Melbourne, Melbourne, Australia.
⁸ 8University of Manchester & Manchester University Hospitals Foundation Trust, Manchester, UK.
⁹ The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
¹⁰ 10Medical Genetics, Cardiff University, Cardiff, UK.
¹¹ University of Newcastle and the Hunter Medical Research Institute, Callaghan, Australia.
¹² 12University of Newcastle, Newcastle upon Tyne, UK.
¹³ 13University Witten-Herdecke, Wuppertal, Germany.
¹⁴ 14Dept. of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
¹⁵ 15Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
¹⁶ 16MGZ- Medical Genetics Center, Munich, Germany.
¹⁷ 17Central Finland Central Hospital, Education and Research, Jyväskylä, Finland.
¹⁸ 18Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
¹⁹ 19Karolinska Institutet, Stockholm, Sweden.
²⁰ 20Hadassah Medical Center, Jerusalem, and Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.
²¹ 21Institute of Human Genetics, University of Bonn, Bonn, Germany.
²² 22Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
²³ 23Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
²⁴ 24Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
²⁵ Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay.
²⁶ Tel-Aviv Soursky Medical Center, Tel-Aviv, Israel.
²⁷ 27Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands.
²⁸ 28Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
²⁹ 29Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
³⁰ 30Medical School, Institute of Human Genetics, Heinrich-Heine-University, Düsseldorf, Germany.
³¹ 31Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
³² 32St Mark's Hospital, Department of Surgery and Cancer, Imperial College London, London, UK.
³³ 33University of Manchester and St Mary's Hospital, Manchester, UK.
³⁴ Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L'Hospitalet de Llobregat, Barcelona, Spain.
³⁵ Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
³⁶ 36University Medical Center Groningen, Groningen, the Netherlands.
³⁷ 37Leids Universitair Medisch Centrum, Leiden, Netherlands.
³⁸ 38Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
³⁹ 39Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ USA.
⁴⁰ 40Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
⁴¹ 41Department of Medical Genetics, Aarhus University Hospital, Aarhus, Denmark.
⁴² 42Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.
⁴³ 43Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
⁴⁴ 44University of Oslo, Oslo, Norway.
⁴⁵ 45Harvard School of Public Health, Boston, MA USA.

PMID: 30858900
PMCID: PMC6394091
DOI: 10.1186/s13053-019-0106-8

Abstract

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.

Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.

Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14).

Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

Keywords: Colonoscopy; Colorectal cancer; Endoscopy; Hereditary cancer; Hereditary nonpolyposis colorectal cancer; Lynch syndrome; Microsatellite instability; Mismatch repair; Over-diagnosis; Screening; Surveillance.

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Conflict of interest statement

All reporting centers obtained informed consent for genetic testing and surveillance procedures. De-identified data was exported for the current study. No named registry needing approval was established for the current study.Not applicable.Toni Seppälä: a co-owner (20%) of Healthfund Finland Oy (educational and health care services in Finland, not related to patients or scope of this manuscript). Travel costs to a scientific meeting by Medtronic Finland. John Burn: a patent for high speed low cost tumor profiling pending to John Burn and QuantuMDx. All others: None declared.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

**Fig. 1**
Number of CRC in different AJCC stages diagnosed in the time interval since the last surveillance colonoscopy. a time since last colonoscopy in intervals of < 1.5, 1.5 to 2.5, 2.5 to 3.5 and > 3.5 years. b Time intervals of less and more than 2.5 years

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Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report

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Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report

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