Should women with Lynch syndrome be offered gynaecological cancer surveillance?
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n2020 (Published 02 September 2021) Cite this as: BMJ 2021;374:n2020
- NAJ Ryan, specialty registrar in obstetrics and gynaecology, clinical lead for Lynch syndrome Southwest Genomic Medicine Service Alliance; honorary clinical lecturer1 2,
- T Snowsill, senior research fellow3,
- E McKenzie, patient representative,
- KJ Monahan, consultant gastroenterologist, honorary senior clinical lecturer4,
- D Nebgen, associate professor and attending gynaecology oncology surgeon5
- 1The Academic Women’s Health Unit, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- 2Department of Obstetrics and Gynaecology, St Michael’s Hospital, Bristol, UK
- 3Health Economics Group, University of Exeter Medical School, University of Exeter, Exeter, Devon, UK
- 4The Lynch Syndrome and Family Cancer Clinic, St Mark’s Hospital and Academic Institute, Harrow, London, UK Imperial College London, London, UK
- 5Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Correspondence to NAJ Ryan neilryan{at}nhs.net
What you need to know
Lynch syndrome is an inherited genetic condition associated with an increased risk of endometrial and ovarian cancer in women
Limited low quality evidence from observational studies show that gynaecological surveillance detects cancers in women with Lynch syndrome; but it is uncertain if this improves survival, and the optimal testing strategy is not established
Inform women with Lynch syndrome about their risk of developing cancer and initiate a discussion about their preference for risk reducing surgery which is definitive, or options for annual review and gynaecological surveillance, explaining their risks and benefits
Guidelines published in 2020 by the National Institute for Health and Care Excellence (NICE) recommend testing for Lynch syndrome in women with endometrial cancer at the time of diagnosis.1 Lynch syndrome is an inherited autosomal dominant condition. 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 The lifetime risk of someone with Lynch syndrome developing any cancer is estimated to be greater than 60% (unless caused by a PMS2 mutation), according to data from the Prospective Lynch Syndrome database (http://www.plsd.eu). For a woman with Lynch syndrome, the lifetime risk of endometrial or ovarian cancer is 40-60% and 10-17%, respectively, the incidence increasing with age beyond 40 years.2
Data sources and selection strategy
We searched CENTRAL, Medline, Embase, and the Cochrane Database of Systematic Reviews for articles in English from the database inception to February 2021. Our search yielded 974 records. After removal of duplicates, 719 were available to screen. Screening was done by two independent reviewers using the Rayyan platform (https://www.rayyan.ai). Of these, 49 underwent full title review. Full manuscripts (not conference abstracts) are summarised in the supplementary table. All the studies identified were observational in nature. Our systematic review also identified four guidelines that addressed gynaecological surveillance in Lynch syndrome carriers; these are detailed in table 1.
UK, US, and European guidelines recommend screening all patients diagnosed with colorectal or endometrial cancer for Lynch syndrome to prevent other cancers through surveillance and to identify relatives with Lynch syndrome.1345 But these guidelines differ in their recommendations regarding gynaecological surveillance (table 1). A nationwide survey in the UK (41 gynaecological oncologists, 298 women with Lynch syndrome) reported widespread variation in gynaecological surveillance practices and risk reducing surgery.10
UK, European, US, and National Comprehensive Cancer Network gynaecological surveillance recommendations for women with Lynch syndrome
Gynaecological surveillance aims to detect pre-malignant disease or early stage cancer to improve survival. It can be carried out either by symptom review, pelvic ultrasound, blind endometrial biopsy, or hysteroscopy with targeted endometrial biopsy. Often a combination of these is used. Prophylactic hysterectomy with bilateral salpingo-oophorectomy remains the mainstay of risk reduction.1112 Some women may prefer to avoid surgery because of the risk of complications13 or may not be fit for surgery. Risk reducing surgery inevitably leads to infertility and a surgical menopause which, without effective hormone replacement therapy, leads to a reduced quality of life and physical health.14
Gynaecological surveillance may offer an alternative but there is uncertainty about the appropriate method and interval in women with Lynch syndrome and whether it improves detection and survival.1015
What is the evidence of uncertainty?
A systematic review published in 2011 (five studies) noted a lack of evidence on gynaecological cancer surveillance in women with Lynch syndrome to guide clinical decision making.16 We found 15 observational studies in our search. These are summarised in the supplementary table. Gynaecological surveillance resulted in detection of both endometrial and ovarian cancers in these studies. In the absence of comparison groups, it is difficult to conclude if surveillance leads to early detection or improves survival. Some women were symptomatic at the time of cancer diagnosis and may have presented even without surveillance. In a study (54 women) with matched controls not undergoing screening, surveillance did not result in earlier cancer detection, and despite screening two women died from ovarian cancer.17 Studies used different testing strategies and are mostly small and retrospective in nature with loss to follow-up and inconsistent methods. Studies have not looked at the harms of screening.
The addition of endometrial sampling improves detection of endometrial pathology compared with transvaginal ultrasound alone.161819 No cancers were missed in studies using outpatient hysteroscopy, endometrial biopsy, and pelvic ultrasound.202122 Of note, all studies that carried out gynaecological surveillance annually reported no missed cancers.16 Cancers were missed in studies where annual surveillance was not performed.232425
It is not possible to apply findings of gynaecological surveillance in the general population to women with Lynch syndrome. Women with Lynch syndrome are likely to undergo surveillance at a younger age and be premenopausal. The histopathology of cancers also differs. The utility of these tests in asymptomatic women is not established.
A well powered prospective observational study using four monthly risk of ovarian cancer algorithm screening in women with a familial risk of ovarian cancer noted it reduced the stage at which ovarian cancer was diagnosed.26 However, only 2.8% of the participants in this study had Lynch syndrome (most had hereditary breast ovarian cancer).
Screening can potentially lead to overdiagnosis. In a study of 140 women, ovarian cancer surveillance led to nine unnecessary operations.27 Endometrial sampling is painful, and the fear of pain can prompt some women to opt for risk reducing surgery sooner then they may have otherwise.28 Outpatient hysteroscopy can have complications such as pain (in 5% of women),29 infection (1%), perforation (0.76%), life threating bleeding (0.02%), and visceral injury (0.01%).3031 Screening can have a psychological impact as reported in a systematic review of individuals with a hereditary risk of cancer.3233
A cost effectiveness analysis in 2011 indicated that prophylactic surgery is less expensive and leads to the highest number of quality adjusted life years when compared with annual gynaecological surveillance in women with Lynch syndrome.34
Is ongoing research likely to provide relevant evidence?
We searched ISRCTN and ClinicalTrials.gov for ongoing trials using the terms “Lynch syndrome” and separately the term “hereditary non-polyposis colorectal cancer.” We found no ongoing studies evaluating surveillance versus no surveillance or different surveillance technologies versus each other. We are conducting a systematic review of gynaecological surveillance in Lynch syndrome (NIHR129713) compared with no surveillance. The review will also note the modality of surveillance and present different estimates of diagnostic performance for the modalities evaluated. It is due to report in 2022.
What should we do in light of the uncertainty?
Inform women with Lynch syndrome of the increased risk of cancers. Offer an annual review to inquire about the cardinal symptoms of gynaecological cancer such as abdominal distension or bloating, loss of appetite, pelvic or abdominal pain, unexplained lower urinary tract symptoms, change in bowel habit, abnormal vaginal bleeding or discharge, and thrombocytosis.35 A discussion about family planning may be appropriate as those with Lynch syndrome may wish to have children earlier to enable timely surgery.36 In women who do not intend to conceive in the future, discuss the option of risk reducing surgery.12
Discuss the options for and the potential risks and benefits of surveillance to enable women to make an informed decision. A study in Finland reported that women with Lynch syndrome found a discussion about gynaecological surveillance beneficial.32 Compliance with gynaecological surveillance performed every 2-3 years was greater than 95% in another Finnish study over 10 years.23 Ideally, endometrial sampling alongside a pelvic ultrasound to enable assessment of the ovaries done at least annually by a gynaecologist might be most effective. Inform women that interval cancers are possible and they should seek urgent medical attention if they develop symptoms. Gynaecologists with expertise in Lynch syndrome may further advise on risk stratification of women for screening and the optimal testing strategy and frequency based on the type of mutation.37
Recommendations for further research
A well designed randomised controlled trial comparing no surveillance or symptom review only versus endometrial sampling and pelvic ultrasound would be ideal. Recruitment may be problematic as participants often elect for active surveillance. An alternative would be a stepped wedge cluster randomised control trial which could be used as gynaecological surveillance services are developed locally. However, as most regions have some degree of ad hoc surveillance, this could be difficult and could suffer from confounding.
The use of novel technologies such as endometrial cytology or molecular analysis to improve disease prediction warrant further exploration.
National databases capturing the clinical outcomes of gynaecological surveillance in individuals with Lynch syndrome should be developed and maintained.
The following recommendations would help improve the quality and usefulness of future research. Studies should
Be adequately powered to identify any significant difference
Follow-up needs to be sufficient (at least 10 years) to be able to capture any survival benefit
Record any complications secondary to surveillance
Have rigorous methods to capture interval cancers
Use methods that include endometrial sampling and imaging of the ovaries
Include measures of patient satisfaction and psychological morbidity instruments
What patients need to know
Having Lynch syndrome puts you at increased risk of womb and ovarian cancer
The degree of risk is dependent on which gene your mutation is in and your age. For a risk calculator see: lscarisk.org
Once your family is complete, and if you can, consider surgery to remove the womb, tubes, and ovaries as this will reduce your risk of gynaecological cancers
Risk reducing surgery can have complications and leads to infertility. Discuss this with your surgeon who can give you information on your personal risk
Be mindful of the symptoms of gynaecological cancer, such as vaginal discharge or unscheduled bleeding, heavier periods, pain, bloating, weight loss, change in bowel habits, decreased appetite or new onset irritable bowel symptoms. If you experience these symptoms seek urgent gynaecological (<2 weeks) review
Your gynaecologist may offer you an annual review to talk about family planning, risk reducing surgery, the use of aspirin, lifestyle measures, and to discuss the pros and cons of gynaecological surveillance for cancers
Evidence is limited on the appropriate testing method and frequency to detect cancers. While annual surveillance reduces the chances of a missed cancer, the testing can be painful for some, and may be costly and difficult to access. Discuss with your gynaecologist the most feasible options for you regarding surveillance and surgery
Education into practice
How will you discuss the pros and cons of gynaecological surveillance with a woman who has Lynch syndrome?
What is the current protocol regarding screening for Lynch syndrome and subsequent gynaecological surveillance at your practice? How does it align with current guidelines?
How patients were involved in the creation of this article
One of our coauthors is a carrier of Lynch syndrome and currently undergoes gynaecological surveillance. She preferred having the option of gynaecological surveillance as it offers a proactive alternative to watch and wait. Risk reducing surgery is not always acceptable to Lynch syndrome carriers. Based on that patient’s input we have emphasised that clinicians must discuss the risks, benefits, and necessity of surveillance or surgery while considering the individual’s context and preferences. We are grateful for the patient’s contribution.
Footnotes
This is one of a series of occasional articles that highlight areas of practice where management lacks convincing supporting evidence. The series adviser is Nai Ming Lai, clinical editor. You can read more about how to prepare and submit an Education article on our Instructions for Authors pages: https://www.bmj.com/about-bmj/resources-authors/article-types
Contributors: NAJR planned the article and wrote the first draft and subsequent revision. NAJR and TS conducted the literature review. EM, KM, and DN critically appraised and revised the article. All authors gave final approval of the version to be published. NAJR, as the guarantor, accepts full responsibility for the work and controlled the decision to publish.
Acknowledgments: We thank Simon Briscoe, University of Exeter, for allowing us to reuse the search strategy from NIHR129713.
Competing interests: We have read and understood the BMJ policy on declaration of interests and have no relevant interests to declare.
Funding: There was no specific funding for this work.
Provenance and peer review: commissioned, based on an idea from the author; externally peer reviewed.