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

Abstract

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.

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

“…The offer of RRS is currently recommended for women with path_MMR variants no earlier than 35-40 years of age 6 (also see Seppala et al, 7 patient 2286). Our intention is to empower individual path_MMR heterozygotes to make an informed choice.…”

“…The recent Manchester International Consensus Group publication 6 described the risk for, and survival after, gynecological cancers in LS by genotype, as initially reported by the Prospective Lynch Syndrome Database (PLSD). [1][2][3][4]7 Later, the PLSD reported findings in an additional independent cohort of path_MMR heterozygotes that validated the results from its original cohort and allowed merger of both cohorts to obtain more precise risk estimates and calculation of 5year and 10-year crude survival after cancer. 2 Risk-reducing surgery (RRS) including total hysterectomy and bilateral salpingo-oophorectomy (BSO) prevents gynecological cancer in Lynch syndrome.…”

How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies

“…All have a significant adverse event profile, but the therapeutic benefit is likely to lead to their rapid uptake, and, in turn, a major impetus towards classification of MMR status in a range of tumours. This will inevitably lead to increased LS detection [ 70 ], and will facilitate germline MMR gene testing of select patients whilst still under acute care, allowing identified LS cases to benefit from not only immune checkpoint blockade therapy [ 3 ], but other acute clinical interventions such as more extensive surgery to reduce risk of metachronous disease [ 264 ].…”

Diagnosis of Lynch Syndrome and Strategies to Distinguish Lynch-Related Tumors from Sporadic MSI/dMMR Tumors

“…As a consequence, tumors from LS patients display MSI and a loss of expression of MMR proteins. Diagnosis of LS is important, since patients with LS benefit from adapted protocols of clinical management with surveillance and more radical surgery [ 5 , 6 , 7 ]. Preventive measures include regular colonoscopic and gynecological surveillance of MMR pathogenic variant carriers, with the frequency and age of initiation dependent on the mutated MMR gene.…”