The additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome
Introduction
Women with Lynch syndrome (LS), previously called Hereditary Non Polyposis Colorectal Cancer (HNPCC), have an autosomal dominant inherited mutation in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. LS is characterized by a high risk and early occurrence of colorectal cancer and extra colonic cancers [1]. The second most common cancer in female LS patients is endometrial cancer.
The estimated cumulative lifetime risk to develop endometrial cancer in women with LS varies in different reports between 21% and 71%. MLH1 and MSH2 mutation carriers have a lifetime risk up to 60% to develop endometrial cancer; carriers of an MSH6 mutation have a risk up to 71%, [1], [2], [3], [4], [5] although lower risks (24%) have been reported as well [6]. For PMS2 mutation carriers, a risk of 15% has been reported [7]. However, series of PMS2 mutation carriers are significantly smaller than those for the other mismatch repair genes and cancer risk therefore less well established. The overall annual incidence rate of developing endometrial cancer after the age of 40 years in LS is 2,5% [8].
The high risk of endometrial cancer in LS and the earlier age of onset, together with a well-detectable and treatable premalignant or early malignant stage, is the reason to consider endometrial cancer screening in these women and their first degree relatives at 50% risk of LS [1], [2], [9], [10]. A few studies have investigated the optimal gynecological screening protocol in women with LS [1], [4], [11], [12], [13]. Interval endometrial carcinomas occurred with annual screening of TVU alone in two studies [4], [11]. In a study by Renkonen et al., mutation carriers were screened with TVU and standard endometrial sampling of the endometrial tissue at an interval of 2–3 years [1]. In their study, eight of fourteen carcinomas and premalignant lesions were diagnosed by endometrial sampling alone. However, despite endometrial sampling during most of the screening visits in this study, three interval carcinomas occurred. The tumour stage and the survival curve were more optimal in the group of patients who underwent screening than in 83 mutation positive endometrial cancers patients who had not attended screening [1]. In 2009 Gerritzen et al. also found significantly more (pre)malignancies in women with standard endometrial sampling together with annual TVU, than in women with screening by TVU alone [12]. It was concluded that TVU alone is insufficient to detect early endometrial cancer in all cases, especially among premenopausal women, and that adding endometrial sampling improves the effectiveness of gynecological screening in women with LS [1], [12]. Recently Manchandra et al. found four (pre)malignant lesions with TVU and outpatient hysteroscopy with endometrial sampling in 41 women with LS. TVU alone detected two of four lesions [13]. In our hospital, the screening protocol was changed in women with LS or first-degree relatives at 50% risk of carrying the LS mutation and endometrial sampling was added to annual TVU from January 1st 2008. During endometrial sampling, some patients experience painful cramping but data about this symptom are lacking from other studies. Data about effectiveness of annual gynecological screening by TVU in women with LS or first degree relatives in our hospital between 1991 and 2002 have been published by Rijcken et al. [4]. In the current study screening data were analyzed of all women with LS or first degree relatives, who were annually screened between January 2003 and June 2012. The aim of the present study is to evaluate the additional value of endometrial sampling to annual TVU as a standard screening procedure in detecting (pre)malignant endometrial lesions in women with LS or first-degree relatives at 50% risk of carrying the LS mutation.
Section snippets
Setting
Since 1991, a gynecological screening program for females with LS and first-degree relatives at 50% risk of carrying the LS mutation was introduced at the Family Cancer Clinic (FCC) of the University Medical Center Groningen at a recommended age to start of 30 years [14]. In all women with LS, a pathogenic mutation in either MLH1, MSH2, MSH6 or PMS2 had been detected using methods published previously [15], [16], [17]. All clinical data from LS carriers and first-degree relatives at 50% risk of
Results
From 2003 to 2012, 61 women were premenopausal and 14 were postmenopausal. The median age at the first gynecological screening was 38 years (range 26–61) and 41 years (range 23–67 years) in periods I and II, respectively. However three women (23–26–26 years of age) received information about the screening program starting from age 30, and asked to be screened during the first visit. At that visit standard gynaecological screening was performed. Two 26 year old women returned for screening according
Discussion
In this study in 75 women, (300 patient years) there was no additional value of endometrial sampling in the early detection of endometrial cancer in women with Lynch syndrome or their first-degree relatives at 50% risk of carrying the LS mutation. There were 266 standard screening visits. In period I (2003–2007), in 117 screening visits, four premalignant endometrial lesions were detected and one endometrial carcinoma (FIGO stage IB). In period II (2008–2012), in 149 screening visits, two
Conflict of Interest Statement
The authors declare that there are no conflicts of interest.
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2023, European Journal of Medical GeneticsMolecular testing in gynecologic cancer
2023, Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing, Second EditionCharacteristics of Lynch syndrome associated ovarian cancer
2018, Gynecologic OncologyCitation Excerpt :The cumulative lifetime risk of ovarian cancer in LS varies between 6 and 12% with a reported mean age at diagnosis of around 45 years [7,11–15]. Endometrial surveillance by transvaginal ultrasound and endometrial sampling can be effective in diagnosing endometrial cancer at a pre-invasive or early stage [9,16,17]. The value of surveillance for ovarian cancer in LS has never been established and is under debate [9,14,18].
BGCS uterine cancer guidelines: Recommendations for practice
2017, European Journal of Obstetrics and Gynecology and Reproductive BiologyCitation Excerpt :The mean age at diagnosis is 47 years, compared to 60 years for non-inherited EC, however in the limited comparison data available it appears that prognosis and survival are similar. The high risk of EC in Lynch syndrome and an earlier age at onset, together with a detectable and treatable premalignant or early malignant stage, is justification for screening in these women [9]. There is no evidence that screening reduces mortality from EC.
Ovarian cancer in Lynch syndrome; A systematic review
2016, European Journal of CancerCitation Excerpt :Due to these high cancer risks, women with LS are regularly surveyed with the aim of early detection of these cancers. Endometrial cancer surveillance could be effective [19–21], however the value of surveillance for ovarian cancer is under debate [19,22]. In general, ovarian cancer surveillance has not been proven effective in the general population and among women with BRCA 1/2 mutations.
Molecular Testing in Gynecologic Cancer
2016, Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing