Lynch syndrome for the gynaecologist

Abstract

Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer.  Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk-reducing strategies.  Surveillance for gynaecological cancer in women with Lynch syndrome remains controversial; more robust data are needed to determine its effectiveness.  Universal testing for Lynch syndrome in endometrial cancer is being adopted by centres across Europe and is the topic of a current review by the National Institute for Health and Care Excellence (NICE); thus, gynaecologists must become familiar with testing strategies and their results.  Testing strategies involve risk stratification of cancers based on phenotypical features and definitive germline testing. Learning objectives  To define the pathogenesis of Lynch syndrome and its associated gynaecological cancers.  To understand the testing strategies for Lynch syndrome in women with gynaecological cancer.  To learn how best to counsel women with Lynch syndrome regarding gynaecological cancer and risk-reducing strategies to enable informed decision-making. Accepted Article This article is protected by copyright. All rights reserved Ethical issues  Offering gynaecological surveillance despite a lack of robust evidence for its clinical effectiveness may falsely reassure women and delay risk-reducing hysterectomy.  Genetic testing may yield variants of unknown significance with ill-defined clinical implications, which can lead to confusion and anxiety.  Genetic testing has implications not only for the individual, but also for the whole family, so expert counselling is crucial.

Detecting endometrial cancer

“…In premenopausal women, anovulatory cycles in polycystic ovary syndrome (PCOS) and obesity are a major risk factor 7 . Lynch syndrome is an autosomal dominant inherited condition of defective DNA mismatch repair, which affects the MSH2 , MLH1 , MSH6 and PMS2 genes 8 . Women with Lynch syndrome have a 25–60% lifetime risk of EC and present at younger ages than women with sporadic EC 9,10 …”

“…Current BGCS guidelines recommend that women with Lynch syndrome are offered annual TVS, hysteroscopy and endometrial biopsy after the age of 35 years; 21 however, the evidence supporting this strategy is limited 8 . Sceptics question the benefit of screening when most EC presents at an early stage and has an excellent overall 5‐year survival rate 60 .…”

“…Current BGCS guidelines recommend that women with Lynch syndrome are offered annual TVS, hysteroscopy and endometrial biopsy after the age of 35 years; 21 however, the evidence supporting this strategy is limited. 8 Sceptics question the benefit of screening when most EC presents at an early stage and has an excellent overall 5-year survival rate. 60 Other highrisk groups include women with class III obesity referred for weight loss management, in whom a high prevalence of occult endometrial abnormalities has been described 61 and breast cancer survivors receiving tamoxifen treatment, although no screening strategy is currently recommended for either group.…”

“…7 Lynch syndrome is an autosomal dominant inherited condition of defective DNA mismatch repair, which affects the MSH2, MLH1, MSH6 and PMS2 genes. 8 Women with Lynch syndrome have a 25-60% lifetime risk of EC and present at younger ages than women with sporadic EC. 9,10 Red flag symptoms for endometrial cancer Postmenopausal bleeding (PMB), defined as vaginal bleeding occurring more than 12 months after the cessation of menstruation at menopause, is the most common red flag symptom for EC.…”

Should women with Lynch syndrome be offered gynaecological cancer surveillance?

“…It is associated with an increased risk of colorectal, endometrial, and ovarian cancers. It is caused by harmful mutations in the DNA mismatch repair genes MLH1 , MSH2 (EPCAM) , MSH6 , or PMS2 2. One in 440 individuals has Lynch syndrome according to US data, and one in 278 individuals based on a study from Denmark 2.…”