Current management of gynaecological cancers in Lynch syndrome: a Prospective Lynch Syndrome Database report

Mev Dominguez-Valentin1, Emma Crosbie2, Christoph Engel3, Stefan Aretz4, Toni T. Seppälä5,6, Finlay Macrae7,8, Ingrid Winship7,8, Gabriel Capella9, Huw Thomas10, Sigve Nakken1, Eivind Hovig1, Maartje Nielsen11, Rolf H Sijmons12, Lucio Bertario13, Bernardo Bonanni14, Maria Grazia Tibiletti15, Giulia Martina Cavestro16, Annika Lindblom17, Nathan Gluck18, Lior Katz19, Karl Heinimann20, Carlos Vaccaro21, Kate Green22, Fiona Lalloo2, James Hill2, Wolff Schmiegel23, Deepak Vangala23, Claudia Perne4,24, Hans-Georg Strauß25, Johanna Tecklenburg26, Elke Holinski-Feder27, Verena Steinke-Lange27, Jukka-Pekka Mecklin28,29, John-Paul Plazzer7, Marta Pineda9, Matilde Navarro9, Joan Brunet Vidal9, Miriam Mints17, Revital Kariv30, Guy Rosner31, Tamara Alejandra Piñero21, María Laura Gonzalez21, Pablo Kalfayan21, Julian Sampson32, D. Gareth Evans2, Pål Møller1

1Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway. 2University of Manchester & Manchester University Hospitals Foundation Trust, Manchester, United Kingdom. 3Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzing, Germany. 4Institute of Human Genetics, University of Bonn, Bonn, Germany. 5Helsinki University Central Hospital, Department of Surgery, Helsinki, Finland. 6University of Helsinki, Helsinki, Finland. 7The Royal Melbourne Hospital, Melbourne, Australia. 8University of Melbourne, Melbourne, Australia. 9Hereditary Cancer Program, Catalan Institute of Oncology, Insititut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L’Hospitalet de Llobregat, Barcelona, Spain, and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain. 10: St Mark’s Hospital, Department of Surgery and Cancer, Imperial College London, London, United Kingdom. 11Leids Universitair Medisch Centrum, Leiden, Leiden, Netherlands. 12Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. 13Scientific Consultant of the Division of Prevention and Genetic Oncology, European Institute of Oncology, Milan, Italy; Fondazione IRCCS Isrtituto nazionale dei Tumor, Milan, Italy. 14Division of Prevention and Genetic Oncology, European Institute of Oncology, Milan, Italy. 15Ospedale di Circolo ASST Settelaghi, Centro di Ricerca tumori eredo-familiari, Università dell’Insubria, Varese, Italy. 16Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy. 17Karolinska Institutet, Stockholm, Stockholm, Sweden. 18Tel-Aviv Sourasky Medical Center, Research Center for Digestive Disorders and Liver Diseases, Tel-Aviv, Israel. 19High Risk and GI Cancer prevention Clinic, Gatro-Oncology Unit, The Department of Gastroenterology, Sheba Medical Center, Sheba, Israel. 20Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. 21Hereditary Cancer Program (PROCANHE) Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. 22: University of Manchester & Manchester University Hospitals Foundation Trust, Manchester, United Kingdom. 23Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany. 24Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. 25Department of Gynecology, University of Halle, Halle, Germany. 26Department of Human Genetics, Hannover Medical School, Hannover, Germany. 27Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany. 28Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland. 29Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland. 30Department of Gastroenterology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 31Department of Gastroenterology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Israel., Tel-Aviv, Israel. 32Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Heath Park, United Kingdom


Background. There are no international guidelines regarding the current management of gynecological cancers in women with Lynch syndrome (LS). A recent international consensus provided comprehensive clinical guidance that women with LS can expect and receive appropriate standards of care.We aimed to globally assess the current practice to manage women with LS across the participating Prospective Lynch Syndrome Database (PLSD) centers.

Methods.We conducted a survey in 27 medical genetics centers, which comprise a total of 16 countries, covering questions regarding risk reducing total hysterectomy and bilateral salpingo-oophorectomy (BSO), the time appropriate to them, pathogenic mismatch repair (path_MMR) gene, and the involvement of stakeholders.

Results.Twenty-one centers completed the survey. Prophylactic hysterectomy was recommended in 20/21 centers for path_MLH1andpath_MSH2carriers with BSO in 19/21 after 35 years of age. For path_MSH6and path_PMS2variants, 14/21 centers recommended prophylactic hysterectomy with BSO. In half of the centers (11/21, 52%), risk-reducing hysterectomy with BSO were advised by stakeholders (mainly gynecologists, genetic counselors and medical geneticists), while in 8/21 (38%) of the centers, these recommendations were advocated. Prescription of estrogen-only hormone replacement therapy (HRT) was offered by 15/21 (71%) centers with a variable age range (35 – 55 years).

Conclusions. Risk-reducing hysterectomy and BSO are globally recommended for path_MLH1and path_MSH2carriers and 67% (14/21) for path_MSH6and path_PMS2carriers, as measures to prevent gynecological cancer in women with path_MMRvariants. Screening women with gynecological cancer for LS is a multidisciplinary responsibility and it is a challenge to define appropriate standards of care.