European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender

doi:10.1002/bjs.11902

Practice Guideline

. 2021 May 27;108(5):484-498.

doi: 10.1002/bjs.11902.

European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender

T T Seppälä^{1

2}, A Latchford^{3

4}, I Negoi⁵, A Sampaio Soares⁶, R Jimenez-Rodriguez⁷, L Sánchez-Guillén⁸, D G Evans⁹, N Ryan^{10

11}, E J Crosbie¹⁰, M Dominguez-Valentin¹², J Burn¹³, M Kloor^{14

15}, M von Knebel Doeberitz^{14

15}, F J B van Duijnhoven¹⁶, P Quirke¹⁷, J R Sampson¹⁸, P Møller^{12

19}, G Möslein^{20

19}; European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP)

Affiliations

¹ Department of Surgery, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.
² Department of Surgical Oncology, Johns Hopkins Hospital, Baltimore Maryland, USA.
³ Department of Cancer and Surgery, Imperial College London, UK.
⁴ St Mark's Hospital, London North West Healthcare NHS Trust, London, UK.
⁵ Department of Surgery, Emergency Hospital of Bucharest, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
⁶ Hospital Prof. Dr Fernando Fonseca, EPE, Lisbon, Portugal.
⁷ Department of Surgery, Hospital Universitario Virgen del Rocío, Seville, Spain.
⁸ Colorectal Unit, Department of General Surgery, Elche University General Hospital Elche, Alicante, Spain.
⁹ Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester University Hospitals NHS Foundation Trust, UK.
¹⁰ Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.
¹¹ Centre for Academic Women's Health, University of Bristol, Bristol, UK.
¹² Department of Tumour Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
¹³ Faculty of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
¹⁴ Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Germany.
¹⁵ Cooperation Unit Applied Tumour Biology, German Cancer Research Centre, Heidelberg, Germany.
¹⁶ Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherlands.
¹⁷ Pathology and Data Analytics, School of Medicine, University of Leeds, Leeds, UK.
¹⁸ Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
¹⁹ University of Witten/Herdecke, Witten, Germany.
²⁰ Centre for Hereditary Tumours, Bethesda Hospital, Duisburg, Germany.

PMID: 34043773
PMCID: PMC10364896
DOI: 10.1002/bjs.11902

Practice Guideline

European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender

T T Seppälä et al. Br J Surg. 2021.

. 2021 May 27;108(5):484-498.

doi: 10.1002/bjs.11902.

Authors

Affiliations

¹ Department of Surgery, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.
² Department of Surgical Oncology, Johns Hopkins Hospital, Baltimore Maryland, USA.
³ Department of Cancer and Surgery, Imperial College London, UK.
⁴ St Mark's Hospital, London North West Healthcare NHS Trust, London, UK.
⁵ Department of Surgery, Emergency Hospital of Bucharest, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
⁶ Hospital Prof. Dr Fernando Fonseca, EPE, Lisbon, Portugal.
⁷ Department of Surgery, Hospital Universitario Virgen del Rocío, Seville, Spain.
⁸ Colorectal Unit, Department of General Surgery, Elche University General Hospital Elche, Alicante, Spain.
⁹ Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester University Hospitals NHS Foundation Trust, UK.
¹⁰ Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.
¹¹ Centre for Academic Women's Health, University of Bristol, Bristol, UK.
¹² Department of Tumour Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
¹³ Faculty of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
¹⁴ Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Germany.
¹⁵ Cooperation Unit Applied Tumour Biology, German Cancer Research Centre, Heidelberg, Germany.
¹⁶ Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherlands.
¹⁷ Pathology and Data Analytics, School of Medicine, University of Leeds, Leeds, UK.
¹⁸ Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
¹⁹ University of Witten/Herdecke, Witten, Germany.
²⁰ Centre for Hereditary Tumours, Bethesda Hospital, Duisburg, Germany.

PMID: 34043773
PMCID: PMC10364896
DOI: 10.1002/bjs.11902

Abstract
in English, Spanish

Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged.

Methods: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds.

Results: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided.

Conclusion: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.

Antecedentes: El síndrome de Lynch (Lynch síndrome, LS) es la predisposición genética más frecuente para el cáncer hereditario, pero es una patología que sigue siendo infradiagnosticada. Recientemente, grandes estudios prospectivos observacionales han permitido comprender mejor la efectividad de la vigilancia mediante colonoscopia y la heterogeneidad del riesgo de cáncer entre genotipos. Se ha reconocido la necesidad de pautas específicas en función de los genes y del género.

Métodos: El Grupo Europeo de Tumores Hereditarios (European Hereditary Tumour Group, EHTG) y la Sociedad Europea de Coloproctología (European Society of Coloproctology, ESCP) desarrollaron un grupo de trabajo multidisciplinar formado por cirujanos, genetistas clínicos y moleculares, patólogos, epidemiólogos, gastroenterólogos y una representación de pacientes para llevar a cabo una revisión para establecer los grados de evidencia. Se utilizó el formato anterior de las “Guías de Mallorca” para revisar las recomendaciones clínicas. El consenso para las declaraciones de la guía se alcanzó tras tres rondas de votación según el método Delphi.

Resultados: Se elaboraron recomendaciones para la identificación clínica y molecular del LS, manejo quirúrgico y endoscópico del cáncer colorrectal asociado con el LS y medidas preventivas para el cáncer. Se hizo hincapié en los aspectos quirúrgicos y gastroenterológicos del espectro del cáncer. Se aprobaron las recomendaciones de consenso de Manchester para el manejo ginecológico. Se distribuyeron resúmenes para profesionales y el público en general.

Conclusión: Se presentan las recomendaciones de la EHTG y ESCP para la identificación de pacientes con LS, vigilancia colorrectal, manejo quirúrgico del cáncer colorrectal, estilo de vida y quimioprevención en LS en las que se obtuvo consenso (> 80%).

Recommendations for clinical and molecular identification of LS, surgical and endoscopic management of LS‐associated colorectal cancer and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum.

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Figures

**Fig. 1**
Summary of core content of the recommendations MMR, mismatch repair; IHC, immunohistochemical; MSI, microsatellite instability; CRC, colorectal cancer; EHTG, European Hereditary Tumour Group; ESCP, European Society of Coloproctology.

**Fig. 2**
Clinical classification of hereditary non-polyposis colorectal cancer and causal genes HNPCC, hereditary non-polyposis colorectal cancer; MMR, mismatch repair.

See this image and copyright information in PMC

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Møller P, Seppälä T, Dowty JG, Haupt S, Dominguez-Valentin M, Sunde L, Bernstein I, Engel C, Aretz S, Nielsen M, Capella G, Evans DG, Burn J, Holinski-Feder E, Bertario L, Bonanni B, Lindblom A, Levi Z, Macrae F, Winship I, Plazzer JP, Sijmons R, Laghi L, Valle AD, Heinimann K, Half E, Lopez-Koestner F, Alvarez-Valenzuela K, Scott RJ, Katz L, Laish I, Vainer E, Vaccaro CA, Carraro DM, Gluck N, Abu-Freha N, Stakelum A, Kennelly R, Winter D, Rossi BM, Greenblatt M, Bohorquez M, Sheth H, Tibiletti MG, Lino-Silva LS, Horisberger K, Portenkirchner C, Nascimento I, Rossi NT, da Silva LA, Thomas H, Zaránd A, Mecklin JP, Pylvänäinen K, Renkonen-Sinisalo L, Lepisto A, Peltomäki P, Therkildsen C, Lindberg LJ, Thorlacius-Ussing O, von Knebel Doeberitz M, Loeffler M, Rahner N, Steinke-Lange V, Schmiegel W, Vangala D, Perne C, Hüneburg R, de Vargas AF, Latchford A, Gerdes AM, Backman AS, Guillén-Ponce C, Snyder C, Lautrup CK, Amor D, Palmero E, Stoffel E, Duijkers F, Hall MJ, Hampel H, Williams H, Okkels H, Lubiński J, Reece J, Ngeow J, Guillem JG, Arnold J, Wadt K, Monahan K, Senter L, Rasmussen LJ, van Hest LP, Ricciardiello L, Kohonen-Corish MRJ, Ligtenberg MJL, Southey M, Aronson M, Zahary… See abstract for full author list ➔ Møller P, et al. Hered Cancer Clin Pract. 2022 Oct 1;20(1):36. doi: 10.1186/s13053-022-00241-1. Hered Cancer Clin Pract. 2022. PMID: 36182917 Free PMC article.
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References

1. Crosbie EJ, Ryan NAJ, Arends MJ, Bosse T, Burn J, Cornes JM. et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genet Med 2019; 21: 2390–2400. - PMC - PubMed
1. Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 2015; 15: 181–194. - PubMed
1. Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009; 76: 1–18. - PMC - PubMed
1. Haraldsdottir S, Rafnar T, Frankel WL, Einarsdottir S, Sigurdsson A, Hampel H. et al. Comprehensive population‐wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat Commun 2017; 8: 1–11. - PMC - PubMed
1. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter‐inhibitory checkpoints. Cancer Discov 2015; 5: 43–51. - PMC - PubMed

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[1] Crosbie EJ, Ryan NAJ, Arends MJ, Bosse T, Burn J, Cornes JM. et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genet Med 2019; 21: 2390–2400. - PMC - PubMed

[2] Crosbie EJ, Ryan NAJ, Arends MJ, Bosse T, Burn J, Cornes JM. et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genet Med 2019; 21: 2390–2400. - PMC - PubMed

[3] Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 2015; 15: 181–194. - PubMed

[4] Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 2015; 15: 181–194. - PubMed

[5] Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009; 76: 1–18. - PMC - PubMed

[6] Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009; 76: 1–18. - PMC - PubMed

[7] Haraldsdottir S, Rafnar T, Frankel WL, Einarsdottir S, Sigurdsson A, Hampel H. et al. Comprehensive population‐wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat Commun 2017; 8: 1–11. - PMC - PubMed

[8] Haraldsdottir S, Rafnar T, Frankel WL, Einarsdottir S, Sigurdsson A, Hampel H. et al. Comprehensive population‐wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat Commun 2017; 8: 1–11. - PMC - PubMed

[9] Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter‐inhibitory checkpoints. Cancer Discov 2015; 5: 43–51. - PMC - PubMed

[10] Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter‐inhibitory checkpoints. Cancer Discov 2015; 5: 43–51. - PMC - PubMed

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European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender

Affiliations

European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender

Authors

Affiliations

Abstract
in English, Spanish

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Abstract in English, Spanish

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Abstract
in English, Spanish