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Factors associated with decision-making on prophylactic hysterectomy and attitudes towards gynecological surveillance among women with Lynch syndrome (LS): a descriptive study

Factors associated with decision-making on prophylactic hysterectomy and attitudes towards... To prevent endometrial carcinoma in Lynch syndrome (LS), regular gynecological surveillance visits and prophylactic surgery are recommended. Previous data have shown that prophylactic hysterectomy is an effective means of cancer prevention, while the advantages and disadvantages of surveillance are somewhat unclear. We aimed to evaluate female LS carriers’ attitudes towards regular gynecological surveillance and factors influencing their decision-making on prophylactic surgery that have not been well documented. Pain experienced during endometrial biopsies was also evaluated. Postal questionnaires were sent to LS carriers undergoing regular gynecological surveillance. Questionnaires were sent to 112 women with LS, of whom 76 responded (68%). Forty-two (55%) had undergone prophylactic hysterectomy by the time of the study. The majority of responders (64/76; 84.2%) considered surveillance appointments beneficial. Pain level during endometrial biopsy was not associated with the decision to undergo prophylactic surgery. The level of satisfaction the women had with the information and advice provided during surveillance was significantly associated with the history of prophylactic hysterectomy (satisfac- tion rate of 73.2% versus 31.8% of nonoperated women, p = 0.003). The women who had undergone prophylactic surgery were older than the nonoperated women both at mutation testing (median of 42.3 years versus 31.6 years, p < 0.001) and at the time of the study (median of 56.9 years versus 46.0 years, respectively, p < 0.001). Women with LS pathogenic variants have positive experiences with gynecological surveillance visits, and their perception of the quality of the information and advice obtained plays an important role in their decision-making concerning prophylactic surgery. Key words Lynch syndrome · HNPCC · Surveillance · Prophylactic surgery Introduction Lynch syndrome (LS), previously called hereditary nonpoly- * Mari H. Kalamo posis colorectal cancer (HNPCC), is a cancer predisposition mari.h.kalamo@pshp.fi syndrome with a dominant inheritance caused by pathogenic 1 (path_) germline variants in the DNA mismatch repair Department of Gynecology and Obstetrics and Cancer (MMR) genes MLH1, MSH2, MSH6, and PMS2 [1]. In addi- Center, Tampere University Hospital, Tampere, Finland 2 tion to the early occurrence of colorectal cancer (CRC), LS Faculty of Medicine and Medical Technology, Tampere is also characterized by certain extracolonic cancers (ECCs), University, Tampere, Finland 3 of which endometrial carcinoma (EC) is the most common Department of Gastrointestinal Surgery, Helsinki University [1]. Carriers of different path_MMR variants exhibit distinct Hospital and University of Helsinki, Helsinki, Finland 4 patterns of cancer risk and survival. The cumulative inci- Department of Surgery, Central Finland Central Hospital, dence of EC for path_MLH1, path_MSH2, path_MSH6 and Jyväskylä, Finland 5 path_PMS2 is 42.7%, 56.7%, 46.2% and 26.4% at the age of Faculty of Sports and Health Sciences, University 75 years, respectively [2]. of Jyväskylä, Jyväskylä, Finland 6 ECs associated with path_MMR variants usually occur at Department of Education and Science, Central Finland younger ages than in the general population. The average age Health Care District, Jyväskylä, Finland Vol.:(0123456789) 1 3 178 M. H. Kalamo et al. at EC diagnosis in women with LS in a recent retrospective 1400 verified germline MMR variant carriers (http://www. series was reported to be 47–49 years (range 26–87) [1, 3]. hnpcc.fi/ ). Healthy women belonging to a Finnish LS family The steepest increase in the cumulative incidence of EC was receive counseling from clinical geneticists and gynecolo- between 50 and 60 years of age in the Prospective Lynch gists. After counseling, the decision to undergo mutation Syndrome Database (PLSD) [2]. testing and its timing are based on the woman’s individual The clinical practice and guidelines for gynecological choice. Regular follow-up of the mutation-positive women surveillance and prophylactic surgery for female LS variant starts after the mutation testing. Prophylactic hysterectomy carriers vary in different countries [4 ]. Common practice is generally recommended for all female mutation carriers in countries performing surveillance in Europe, Australia, after 35–40 years of age, when the mutation carrier is no North America and South America is either annual on bian- longer wishing for a pregnancy. Surgery is recommended by nual gynecological examination [5]. Based on current pub- the age of menopause at the latest. If prophylactic surgery lished studies, there are no adequate data for evidence-based has not been performed by the age of 40, annual follow-up clinical decisions based on findings during surveillance [6 ]. visits are recommended. The removal of the ovaries is dis- In Finland, after predictive genetic testing was nationally cussed with mutation carriers and is usually performed if the introduced in 1995, annual gynecological examinations woman is peri- or postmenopausal or if she, after receiving have become common clinical practice, including pelvic information, decides to have them removed before meno- ultrasound examination and endometrial biopsy, starting at pause. Finally, salpingo-oophorectomy is recommended at approximately 35 years of age [7]. Prophylactic surgery, or the time of menopause at the latest. hysterectomy with or without bilateral salpingo-oophorec- One hundred and twelve female LS carriers at least 30 tomy or salpingectomy, has usually been performed after years of age, with no history of endometrial or ovarian the age of 40 years, when having children is complete, or at cancer and having previously consented regarding registry the age of menopause, depending on the mutation carrier’s inquiries, were identified from the LSRFi. The study cohort preference [3, 4]. However, some pathogenic variant carri- is described in Table 1. A postal questionnaire was sent to ers disagree with the surgery recommendation and refuse to these 112 women and was re-sent to those who did not return undergo prophylactic hysterectomy. The cancer-preventing questionnaires within 6 months of the first mailing. effects of prophylactic surgery have been proven by clinical trials [6]. A few previous studies have evaluated the process Questionnaires of decision-making on prophylactic surgery, the effects of gynecological surveillance and prophylactic hysterectomy Study participants completed a retrospective questionnaire on the quality of life, and the pain associated with endome- collecting data on their history of other types of cancer, trial sampling of the mutation carriers [4, 8–10]. Since data on the attitudes of LS mutation carriers Table 1 Characteristics of the LS cohort (112 Finnish females with a towards prophylactic surgery and gynecological surveil- path_MMR variant) lance are limited and even absent in Finland, we wanted Whole Study popula- to evaluate the decision-making process, satisfaction with LS cohort tion (responders) surveillance, and pain associated with endometrial biopsies (N = 112) (N = 76) in this questionnaire-based study. Age  Median (range) 49 (30–89) 52 (30–82) Age at mutation testing Materials and methods  Median 38 (20–72) 36 (22–65) Distribution of MMR genes Study subjects  MLH1 72 (64%) 47 (62%)  MSH2 32 (29%) 22 (29%) The present retrospective cohort study was performed at  MSH6 8 (7%) 7 (9%) Tampere University Hospital (TAUH), Tampere, Finland. History of other cancer (Y/N) Informed consent was obtained from all study participants,  Y 42 (38%) 24 (33%) and the study protocol was approved by the TAUH Ethical  N 70 (62%) 49 (67%) Committee (decision code ETL R10079, dated 4.1.2011). Prophylactic surgery performed The study cohort included Finnish women with inher-  Y 63 (56%) 42 (68%) ited pathogenic MMR gene variants identified from the  N 49 (44%) 24 (32%) nationwide Finnish LS Registry (LSRFi), [11] which has been described in more detail previously [12, 13, 14, 15]. LS Lynch syndrome, path_MMR pathogenic variant of DNA mis- Briefly, the LSRFi includes 300 families and approximately match repair gene 1 3 Factors associated with decision-making on prophylactic hysterectomy and attitudes towards… 179 family history, parity, and age at mutation testing and pro- deliveries) in the statistical analyses. When assessing factors phylactic gynecological surgery, if performed. Data on the possibly influencing prophylactic surgery decision-making, subjects’ attitudes towards gynecological surveillance and patients who had a hysterectomy for nonprophylactic reasons prophylactic surgery and their experiences with these proce- were excluded from the analyses. dures were also collected. Pain associated with endometrial biopsies was evaluated with a numeric rating scale (NRS; 0–10, 0 = no pain and 10 = worst imaginable pain). Subjects Results who stated they could not recall or evaluate the pain level did not answer this question. A detailed description of the Seventy-six women returned the questionnaire, resulting in a questionnaire content is presented in Table 2. 68% response rate. The distribution of the affected genes was as follows: 62% MLH1, 29% MSH2 and 9% MSH6 muta- Statistical analysis tions. A prophylactic hysterectomy was performed on 42 subjects of this population (55%) at the median age of 42.0 IBM SPSS statistics software, version 22 (IBM SPSS, Inc., years (range 32.0–67.0). Twenty-four subjects had not had Armonk, NY, USA), was used for the statistical analyses. a hysterectomy at the time of the survey, and 10 subjects The association of categorized variables with prophylactic had a nonprophylactic hysterectomy performed for benign surgery decisions was performed using the chi-squared test. medical reasons, such as uterine myomas, menorrhagia with- Two-tailed P < 0.05 values were considered to indicate sta- out endometrial hyperplasia, and pelvic floor prolapses, for tistically significant differences. The association of continu- which they were excluded from the analyses concerning ous variables (e.g., NRS and number of deliveries) with the prophylactic hysterectomy. The characteristics of the study history of prophylactic surgery was carried out using the t cohort (both responders and nonresponders) are summarized test or a nonparametric test when appropriate. NRS scores in Table 1. and the number of deliveries were also categorized (NRS Among subjects not having had a hysterectomy per- 0 to 5 versus 6 or more and parity of 0 versus 1 or more formed at the time of the study, eight (33.3%) reported they Table 2 Details of the questionnaire used Feature Further information Measurement/response Time of predictive testing Date/year Age at predictive testing Number Relationship status before testing In a relationship? Y/N Relationship status on study In a relationship? Y/N Prophylactic surgery performed Y/N Has attended follow-up appointments Y/N Considers follow-up beneficial If “yes” to previous Y/N Parity Number of deliveries Number Experienced pain in endometrial biopsy NRS 0–10 Number Satisfied with the advice provided by the professionals In general Y/N Enough information provided on possible adverse effects of prophy - Gynecological prolapses Y/N lactic surgery Urinating complaints Y/N G-I tract complaints Y/N Has felt pressure for prophylactic surgery Y/N Satisfied with decision to have surgery If performed Y/N Planning to have prophylactic surgery If not performed Y/N Cancer other than gynecological cancer in family Personal history or family member Y/N Which cancer Description Family member died of gynecological cancer Y/N Experience of personal state of health Poor/intermediate/good 0/1/2 Poor tolerance of insecurity Own experience Y/N Strong fear of cancer Y/N Strong fear of surgery/operations Y/N Experience of surgery as responsibility Y/N 1 3 180 M. H. Kalamo et al. were not planning to have a prophylactic hysterectomy at all, time interval between surgery and the study questionnaire and 16 (66.7%) reported not having decided yet about the was 9 years (1–38 years) among the prophylactically oper- surgery or did not respond. ated subjects. The median age at mutation testing among subjects with a Sixty-eight (89.5%) of the responders reported attending prophylactic hysterectomy performed was 42.3 years (range regular surveillance appointments that were provided. Six 25–65), compared to 31.6 years (range 22–48) for subjects subjects reported not having been offered appointments at with no hysterectomy performed (p < 0.001). At the time all, and two subjects did not respond to this question. Sixty- of the study, the median age of subjects with a prophylac- four (84.2%) of the subjects considered appointments to be tic hysterectomy performed was 56.9 years (range 43–72), beneficial, 10 subjects did not respond to this question and compared to 43.2 years (range 30–76) for subjects with no only two patients considered appointments unbeneficial. hysterectomy performed (p < 0.001). Pain associated with endometrial sampling measured by The median time interval between mutation testing and NRS, overall satisfaction with the given information and the study survey was 11 years (range 6–29 years) among the all the background factors possibly having an influence on study subjects still in surveillance (not having undergone women’s attitudes and decisions on prophylactic surgery prophylactic surgery). The median duration of surveillance obtained from the questionnaires are summarized in Table 3. (median time interval between mutation testing and prophy- Fifty-four subjects evaluated pain associated with endome- lactic surgery) was 6 years (0–14 years), and the median trial biopsy, while 22 (29%) of the subjects did not respond Table 3 Background characteristics and factors collected from questionnaires obtained from prophylactically operated vs. nonoperated mutation carriers Reported variables Study population Prophylactic hysterectomy Nonoperated (N = 24)p value a b (N = 76) performed (N = 42) n (%) n (%) n(%) 1. Parity: 1 or more deliveries 66 (86.8) 37 (88.1) 21 (87.5) 1.000 2. Own health considered intermediate or good 50 (65.8) 24 (58.5) 18 (75.0) 0.282 3. In a relationship at mutation diagnosis 67 (88.2) 40 (95.2) 19 (79.2) 0.089 4. Attended gynecological appointments regularly 68 (89.5) 37 (88.1) 21 (87.5) 1.000 5. Cancer other than gynecological cancer in family 73 (96.0) 39 (92.9) 24 (100.0) 0.295 6. Family member died of gynecological cancer 17 (22.3) 12 (29.3) 4 (16.7) 0.373 7. Poor tolerance of feeling of insecurity 13 (17.1) 5 (11.9) 5 (20.8) 0.477 8. Strong fear of cancer 32 (42.1) 19 (45.2) 10 (41.7) 0.803 9. Strong fear of surgery/operations 12 (15.7) 6 (14.3) 4 (16.7) 1.000 10. Experience of surgery as responsibility 16 (21.0) 12 (29.3) 3 (12.5) 0.142 11. Feels/has felt pressure for surgery 20 (26.3) 14 (35.9) 5 (22.7) 0.391 12. Satisfied with information and advice in general 43 (56.6) 30 (73.2) 7 (31.8) 0.003 13. Satisfied with information on possible postoperative disadvantages a. Urinary complaints 18 (23.6) 11 (28.9) 2 (9.1) 0.106 b. Chronic pelvic pain 20 (26.3) 12 (31.6) 3 (13.6) 0.215 c. GI-tract complaints 19 (25.0) 12 (31.6) 2 (9.1) 0.061 d. Pelvic prolapses 19 (25.0) 12 (31.6) 2 (9.1) 0.061 d d d 14. Endometrial biopsy pain (NRS score) (N = 54) (N = 28) (N = 19) a. 0–5 39 (72.2) 21 (75.0) 11 (57.9) b. 6–10 15 (27.8) 7 (25.0) 8 (42.1) 0.339 15. Median age, years Year (range) Year (range) Year (range) a. At mutation testing 35.2 (22–65) 42.3 (25–65) 31.6 (22–48) < 0.001 b. At survey 48.8 (30–76) 56.9 (43–72) 43.2 (30–76) < 0.001 Defined by study questionnaire responders 10 subjects with nonprophylactic hysterectomy excluded from comparison Comparison between nonoperated and prophylactically operated subjects Total of 54 subjects answered this question (22 subjects did not respond) 1 3 Factors associated with decision-making on prophylactic hysterectomy and attitudes towards… 181 to this question. The median NRS among Women with LS not a significant factor for decision-making, at least in our was 3.5. Most women (72.2%) reported mild or intermedi- study population. The association of older age at mutation ate pain associated with endometrial biopsy measured by testing and at survey was expected since all recommenda- NRS (NRS 0–5), and strong pain (NRS 6–10) was reported tions for the initiation of surveillance and the timing of pro- by 27.8% of women. Approximately 40% of participants phylactic surgery are age-dependent. reported pain to be very mild or there was no pain at all The majority of subjects considered gynecological sur- (NRS 0 to 2). Pain levels during endometrial biopsy did veillance to be beneficial in general. There have been some not influence the rate of prophylactic surgeries when ana- previous qualitative studies on the topic showing experi- lyzed either as a continuous variable or when categorized. enced benefit [8, 10]. We show that some of the study Regardless of the history of prophylactic hysterectomy, a subjects reported being either inadequately or not at all majority of women (43/76; 59.7%) reported satisfaction informed about the risks and possible long-term side effects with the information and advice regarding LS in general and of prophylactic surgery. Earlier qualitative studies evaluat- prophylactic surgery provided by gynecologists. Only four ing surgery decisions have reported similar results: muta- subjects did not answer this question. The self-reported sat- tion carriers are mainly satisfied with prophylactic surgery isfaction with general LS-associated information and advice decisions, but nonoperated women are not completely satis- by experts was dependent on the history of prophylactic fied with the information they receive [6 , 8]. One possible hysterectomy: 73.2% of the operated patients were satisfied explanation for this is that more detailed surgery-related versus only 31.8% of the nonoperated patients (p = 0.003; information is provided only when the decision to undergo Table 3). The compliance rate with gynecological surveil- surgery has been made. From this retrospective analysis, it lance was similar among operated and nonoperated women is not possible to draw straightforward conclusions, but it is (88.1% versus 87.5%, respectively, p = 1.00; Table 3). probable that women with LS may warrant more detailed In addition, there was a trend for women who chose pro- and structured information on surgery during surveillance. phylactic hysterectomy to have received more information Some of our study subjects were not satisfied with the on certain postoperative complications than women who had surveillance protocol. A few LS carriers reported not being not chosen surgery yet (p = 0.061 for information on GI-tract informed at all about gynecological surveillance appoint- postoperative complications and pelvic prolapses; Table 3). ments. This probably influenced their decision-making on prophylactic surgery and may have led them to refuse it, thus keeping them susceptible to EC. This finding emphasizes the Discussion importance of structured national guidelines for the manage- ment of LS. In this study, LS pathogenic variant carriers’ attitudes The strengths of our study include a well-defined popula- towards gynecological surveillance and satisfaction with tion of women with LS who were all verified as germline the advice and information provided by experts were sig- pathogenic variant carriers and were not just women who nificantly associated with having had prophylactic surgery. had a strong family history of EC or CRC. The study cohort To our knowledge, this finding highlights the importance of identified from the LSRFi included 112 women, and the general information in this context and emphasizes the role response rate was quite high (68%), which is in line with of attending medical staff. On the other hand, compliance previous questionnaire-based studies among subjects with with surveillance was similar between prophylactically oper- a hereditary cancer predisposition [14, 15]. ated and nonoperated women, suggesting that the quality of There are some limitations to our study. The setting is ret- information may play a significant role in decision-making. rospective, and a questionnaire survey is subject to the risk Parity and experienced pain during endometrial sampling of misremembering background factors. This misremember- did not correlate with the decision to undergo prophylactic ing may therefore cause recall bias. However, we consider surgery. A previous study indicated that parity influences that a questionnaire-based survey is also a valuable method decision-making, but the data were derived from a very to collect the points of view and experiences of women with small study population of ten women with LS [8]. Severe LS. Prophylactically operated subjects were expectedly sig- pain experienced during endometrial sampling has been pre- nificantly older at the time of mutation diagnosis and at viously shown to be the main reason to quit screening, thus study than nonoperated women, which can also cause some possibly lowering the threshold for surgery [10]. Different bias. A comparison of responders to nonresponders did not populations may explain differences in the results concern- reveal any major concerns other than the slightly more fre- ing the experience of pain during endometrial sampling. quent rate of prophylactic hysterectomy among the respond- Since ultrasound examination is not sufficient as a single ers, which may cause potential bias and must be taken into surveillance method in terms of EC prevention, [16] it is a account when interpreting the present results. Some of relief that pain associated with endometrial sampling was the study subjects had a hysterectomy for nonprophylactic 1 3 182 M. H. Kalamo et al. 4. Herzig DO et al (2017) Clinical practice guidelines for the surgi- reasons, and they had to be excluded from the analyses when cal treatment of patients with lynch syndrome. Dis Colon Rectum estimating the factors influencing the decision-making about 60(2):137–143 prophylactic surgery. 5. Møller P et al (2017) Cancer incidence and survival in Lynch In conclusion, we show here new descriptive data on the syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome attitudes towards surveillance and factors associated with the database. Gut 66(3):464–472 history of prophylactic surgery in a Finnish cohort of women 6. Schmeler KM et al (2006) Prophylactic surgery to reduce the risk with LS. Based on our results, surveillance is well accepted. of gynecologic cancers in the Lynch syndrome. N Engl J Med Considering the results of our study, we suggest that the 354(3):261–269 7. Nyström-Lahti M et  al (1995) Founding mutations and alu- mutation carriers should be systematically informed about mediated recombination in hereditary colon cancer. Nat Med surveillance and its aims and about prophylactic surgery. We 1(11):1203–1206 suggest that information should be offered regardless of the 8. Etchegary H, Dicks E, Watkins K, Alani S, Dawson L (2015) timing of the prophylactic surgery. Decisions about prophylactic gynecologic surgery: a qualitative study of the experience of female Lynch syndrome mutation car- riers. Hered Cancer Clin Pract 13(1):10 9. Etchegary H, Dicks E, Tamutis L, Dawson L (2018) Quality of Funding Pirkanmaa Hospital District’s Research Funding, Cancer life following prophylactic gynecological surgery: experiences of Society of Finland. female Lynch mutation carriers. Fam Cancer 17(1):53–61 10. Helder-Woolderink J, de Bock G, Hollema H, van Oven M, Mour- Compliance with ethical standards its M (2017) Pain evaluation during gynaecological surveillance in women with Lynch syndrome. Fam Cancer 16(2):205–210 11. Järvinen HJ, Renkonen-Sinisalo L, Aktán-Collán K, Peltomäki P, Conflict of interest The authors declare that they have no competing Aaltonen LA, Mecklin J-P (2009) Ten years after mutation testing interest. for lynch syndrome: cancer incidence and outcome in mutation- positive and mutation-negative family members. J Clin Oncol Open Access This article is licensed under a Creative Commons Attri- 27(28):4793–4797 bution 4.0 International License, which permits use, sharing, adapta- 12. Mecklin JP (1987) Frequency of hereditary colorectal carcinoma. tion, distribution and reproduction in any medium or format, as long Gastroenterology 93(5):1021–1025 as you give appropriate credit to the original author(s) and the source, 13. Gylling A et  al (2009) Large genomic rearrangements and provide a link to the Creative Commons licence, and indicate if changes germline epimutations in Lynch syndrome. Int J Cancer were made. The images or other third party material in this article are 124(10):2333–2340 included in the article’s Creative Commons licence, unless indicated 14. Staff S, Aaltonen M, Huhtala H, Pylvänäinen K, Mecklin J-P, otherwise in a credit line to the material. If material is not included in Mäenpää J (2016) Endometrial cancer risk factors among Lynch the article’s Creative Commons licence and your intended use is not syndrome women: a retrospective cohort study. Br J Cancer permitted by statutory regulation or exceeds the permitted use, you will 115(3):375–381 need to obtain permission directly from the copyright holder. To view a 15. Aaltonen MH, Staff S, Mecklin J-P, Pylvänäinen K, Mäenpää JU copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. (2017) Comparison of lifestyle, hormonal and medical factors in women with sporadic and Lynch syndrome-associated endo- metrial cancer: a retrospective case-case study. Mol Clin Oncol 6(5):758–764 References 16. Auranen A, Joutsiniemi T (May 2011) A systematic review of gynecological cancer surveillance in women belonging to heredi- 1. Aarnio M et al (1999) Cancer risk in mutation carriers of DNA- tary nonpolyposis colorectal cancer (Lynch syndrome) families. mismatch-repair genes. Int J Cancer 81(2):214–218 Acta Obstet Gynecol Scand 90(5):437–444 2. Møller P et al (2018) Cancer risk and survival in path_MMR car- riers by gene and gender up to 75 years of age: a report from the Publisher’s Note Springer Nature remains neutral with regard to prospective lynch syndrome database. Gut 67(7):1306–1316 jurisdictional claims in published maps and institutional affiliations. 3. Lu KH, Daniels M (2013) Endometrial and ovarian cancer in women with Lynch syndrome: update in screening and preven- tion. Fam Cancer 12(2):273–277 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Familial Cancer Springer Journals

Factors associated with decision-making on prophylactic hysterectomy and attitudes towards gynecological surveillance among women with Lynch syndrome (LS): a descriptive study

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Copyright © The Author(s) 2020
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1389-9600
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10.1007/s10689-020-00158-5
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Abstract

To prevent endometrial carcinoma in Lynch syndrome (LS), regular gynecological surveillance visits and prophylactic surgery are recommended. Previous data have shown that prophylactic hysterectomy is an effective means of cancer prevention, while the advantages and disadvantages of surveillance are somewhat unclear. We aimed to evaluate female LS carriers’ attitudes towards regular gynecological surveillance and factors influencing their decision-making on prophylactic surgery that have not been well documented. Pain experienced during endometrial biopsies was also evaluated. Postal questionnaires were sent to LS carriers undergoing regular gynecological surveillance. Questionnaires were sent to 112 women with LS, of whom 76 responded (68%). Forty-two (55%) had undergone prophylactic hysterectomy by the time of the study. The majority of responders (64/76; 84.2%) considered surveillance appointments beneficial. Pain level during endometrial biopsy was not associated with the decision to undergo prophylactic surgery. The level of satisfaction the women had with the information and advice provided during surveillance was significantly associated with the history of prophylactic hysterectomy (satisfac- tion rate of 73.2% versus 31.8% of nonoperated women, p = 0.003). The women who had undergone prophylactic surgery were older than the nonoperated women both at mutation testing (median of 42.3 years versus 31.6 years, p < 0.001) and at the time of the study (median of 56.9 years versus 46.0 years, respectively, p < 0.001). Women with LS pathogenic variants have positive experiences with gynecological surveillance visits, and their perception of the quality of the information and advice obtained plays an important role in their decision-making concerning prophylactic surgery. Key words Lynch syndrome · HNPCC · Surveillance · Prophylactic surgery Introduction Lynch syndrome (LS), previously called hereditary nonpoly- * Mari H. Kalamo posis colorectal cancer (HNPCC), is a cancer predisposition mari.h.kalamo@pshp.fi syndrome with a dominant inheritance caused by pathogenic 1 (path_) germline variants in the DNA mismatch repair Department of Gynecology and Obstetrics and Cancer (MMR) genes MLH1, MSH2, MSH6, and PMS2 [1]. In addi- Center, Tampere University Hospital, Tampere, Finland 2 tion to the early occurrence of colorectal cancer (CRC), LS Faculty of Medicine and Medical Technology, Tampere is also characterized by certain extracolonic cancers (ECCs), University, Tampere, Finland 3 of which endometrial carcinoma (EC) is the most common Department of Gastrointestinal Surgery, Helsinki University [1]. Carriers of different path_MMR variants exhibit distinct Hospital and University of Helsinki, Helsinki, Finland 4 patterns of cancer risk and survival. The cumulative inci- Department of Surgery, Central Finland Central Hospital, dence of EC for path_MLH1, path_MSH2, path_MSH6 and Jyväskylä, Finland 5 path_PMS2 is 42.7%, 56.7%, 46.2% and 26.4% at the age of Faculty of Sports and Health Sciences, University 75 years, respectively [2]. of Jyväskylä, Jyväskylä, Finland 6 ECs associated with path_MMR variants usually occur at Department of Education and Science, Central Finland younger ages than in the general population. The average age Health Care District, Jyväskylä, Finland Vol.:(0123456789) 1 3 178 M. H. Kalamo et al. at EC diagnosis in women with LS in a recent retrospective 1400 verified germline MMR variant carriers (http://www. series was reported to be 47–49 years (range 26–87) [1, 3]. hnpcc.fi/ ). Healthy women belonging to a Finnish LS family The steepest increase in the cumulative incidence of EC was receive counseling from clinical geneticists and gynecolo- between 50 and 60 years of age in the Prospective Lynch gists. After counseling, the decision to undergo mutation Syndrome Database (PLSD) [2]. testing and its timing are based on the woman’s individual The clinical practice and guidelines for gynecological choice. Regular follow-up of the mutation-positive women surveillance and prophylactic surgery for female LS variant starts after the mutation testing. Prophylactic hysterectomy carriers vary in different countries [4 ]. Common practice is generally recommended for all female mutation carriers in countries performing surveillance in Europe, Australia, after 35–40 years of age, when the mutation carrier is no North America and South America is either annual on bian- longer wishing for a pregnancy. Surgery is recommended by nual gynecological examination [5]. Based on current pub- the age of menopause at the latest. If prophylactic surgery lished studies, there are no adequate data for evidence-based has not been performed by the age of 40, annual follow-up clinical decisions based on findings during surveillance [6 ]. visits are recommended. The removal of the ovaries is dis- In Finland, after predictive genetic testing was nationally cussed with mutation carriers and is usually performed if the introduced in 1995, annual gynecological examinations woman is peri- or postmenopausal or if she, after receiving have become common clinical practice, including pelvic information, decides to have them removed before meno- ultrasound examination and endometrial biopsy, starting at pause. Finally, salpingo-oophorectomy is recommended at approximately 35 years of age [7]. Prophylactic surgery, or the time of menopause at the latest. hysterectomy with or without bilateral salpingo-oophorec- One hundred and twelve female LS carriers at least 30 tomy or salpingectomy, has usually been performed after years of age, with no history of endometrial or ovarian the age of 40 years, when having children is complete, or at cancer and having previously consented regarding registry the age of menopause, depending on the mutation carrier’s inquiries, were identified from the LSRFi. The study cohort preference [3, 4]. However, some pathogenic variant carri- is described in Table 1. A postal questionnaire was sent to ers disagree with the surgery recommendation and refuse to these 112 women and was re-sent to those who did not return undergo prophylactic hysterectomy. The cancer-preventing questionnaires within 6 months of the first mailing. effects of prophylactic surgery have been proven by clinical trials [6]. A few previous studies have evaluated the process Questionnaires of decision-making on prophylactic surgery, the effects of gynecological surveillance and prophylactic hysterectomy Study participants completed a retrospective questionnaire on the quality of life, and the pain associated with endome- collecting data on their history of other types of cancer, trial sampling of the mutation carriers [4, 8–10]. Since data on the attitudes of LS mutation carriers Table 1 Characteristics of the LS cohort (112 Finnish females with a towards prophylactic surgery and gynecological surveil- path_MMR variant) lance are limited and even absent in Finland, we wanted Whole Study popula- to evaluate the decision-making process, satisfaction with LS cohort tion (responders) surveillance, and pain associated with endometrial biopsies (N = 112) (N = 76) in this questionnaire-based study. Age  Median (range) 49 (30–89) 52 (30–82) Age at mutation testing Materials and methods  Median 38 (20–72) 36 (22–65) Distribution of MMR genes Study subjects  MLH1 72 (64%) 47 (62%)  MSH2 32 (29%) 22 (29%) The present retrospective cohort study was performed at  MSH6 8 (7%) 7 (9%) Tampere University Hospital (TAUH), Tampere, Finland. History of other cancer (Y/N) Informed consent was obtained from all study participants,  Y 42 (38%) 24 (33%) and the study protocol was approved by the TAUH Ethical  N 70 (62%) 49 (67%) Committee (decision code ETL R10079, dated 4.1.2011). Prophylactic surgery performed The study cohort included Finnish women with inher-  Y 63 (56%) 42 (68%) ited pathogenic MMR gene variants identified from the  N 49 (44%) 24 (32%) nationwide Finnish LS Registry (LSRFi), [11] which has been described in more detail previously [12, 13, 14, 15]. LS Lynch syndrome, path_MMR pathogenic variant of DNA mis- Briefly, the LSRFi includes 300 families and approximately match repair gene 1 3 Factors associated with decision-making on prophylactic hysterectomy and attitudes towards… 179 family history, parity, and age at mutation testing and pro- deliveries) in the statistical analyses. When assessing factors phylactic gynecological surgery, if performed. Data on the possibly influencing prophylactic surgery decision-making, subjects’ attitudes towards gynecological surveillance and patients who had a hysterectomy for nonprophylactic reasons prophylactic surgery and their experiences with these proce- were excluded from the analyses. dures were also collected. Pain associated with endometrial biopsies was evaluated with a numeric rating scale (NRS; 0–10, 0 = no pain and 10 = worst imaginable pain). Subjects Results who stated they could not recall or evaluate the pain level did not answer this question. A detailed description of the Seventy-six women returned the questionnaire, resulting in a questionnaire content is presented in Table 2. 68% response rate. The distribution of the affected genes was as follows: 62% MLH1, 29% MSH2 and 9% MSH6 muta- Statistical analysis tions. A prophylactic hysterectomy was performed on 42 subjects of this population (55%) at the median age of 42.0 IBM SPSS statistics software, version 22 (IBM SPSS, Inc., years (range 32.0–67.0). Twenty-four subjects had not had Armonk, NY, USA), was used for the statistical analyses. a hysterectomy at the time of the survey, and 10 subjects The association of categorized variables with prophylactic had a nonprophylactic hysterectomy performed for benign surgery decisions was performed using the chi-squared test. medical reasons, such as uterine myomas, menorrhagia with- Two-tailed P < 0.05 values were considered to indicate sta- out endometrial hyperplasia, and pelvic floor prolapses, for tistically significant differences. The association of continu- which they were excluded from the analyses concerning ous variables (e.g., NRS and number of deliveries) with the prophylactic hysterectomy. The characteristics of the study history of prophylactic surgery was carried out using the t cohort (both responders and nonresponders) are summarized test or a nonparametric test when appropriate. NRS scores in Table 1. and the number of deliveries were also categorized (NRS Among subjects not having had a hysterectomy per- 0 to 5 versus 6 or more and parity of 0 versus 1 or more formed at the time of the study, eight (33.3%) reported they Table 2 Details of the questionnaire used Feature Further information Measurement/response Time of predictive testing Date/year Age at predictive testing Number Relationship status before testing In a relationship? Y/N Relationship status on study In a relationship? Y/N Prophylactic surgery performed Y/N Has attended follow-up appointments Y/N Considers follow-up beneficial If “yes” to previous Y/N Parity Number of deliveries Number Experienced pain in endometrial biopsy NRS 0–10 Number Satisfied with the advice provided by the professionals In general Y/N Enough information provided on possible adverse effects of prophy - Gynecological prolapses Y/N lactic surgery Urinating complaints Y/N G-I tract complaints Y/N Has felt pressure for prophylactic surgery Y/N Satisfied with decision to have surgery If performed Y/N Planning to have prophylactic surgery If not performed Y/N Cancer other than gynecological cancer in family Personal history or family member Y/N Which cancer Description Family member died of gynecological cancer Y/N Experience of personal state of health Poor/intermediate/good 0/1/2 Poor tolerance of insecurity Own experience Y/N Strong fear of cancer Y/N Strong fear of surgery/operations Y/N Experience of surgery as responsibility Y/N 1 3 180 M. H. Kalamo et al. were not planning to have a prophylactic hysterectomy at all, time interval between surgery and the study questionnaire and 16 (66.7%) reported not having decided yet about the was 9 years (1–38 years) among the prophylactically oper- surgery or did not respond. ated subjects. The median age at mutation testing among subjects with a Sixty-eight (89.5%) of the responders reported attending prophylactic hysterectomy performed was 42.3 years (range regular surveillance appointments that were provided. Six 25–65), compared to 31.6 years (range 22–48) for subjects subjects reported not having been offered appointments at with no hysterectomy performed (p < 0.001). At the time all, and two subjects did not respond to this question. Sixty- of the study, the median age of subjects with a prophylac- four (84.2%) of the subjects considered appointments to be tic hysterectomy performed was 56.9 years (range 43–72), beneficial, 10 subjects did not respond to this question and compared to 43.2 years (range 30–76) for subjects with no only two patients considered appointments unbeneficial. hysterectomy performed (p < 0.001). Pain associated with endometrial sampling measured by The median time interval between mutation testing and NRS, overall satisfaction with the given information and the study survey was 11 years (range 6–29 years) among the all the background factors possibly having an influence on study subjects still in surveillance (not having undergone women’s attitudes and decisions on prophylactic surgery prophylactic surgery). The median duration of surveillance obtained from the questionnaires are summarized in Table 3. (median time interval between mutation testing and prophy- Fifty-four subjects evaluated pain associated with endome- lactic surgery) was 6 years (0–14 years), and the median trial biopsy, while 22 (29%) of the subjects did not respond Table 3 Background characteristics and factors collected from questionnaires obtained from prophylactically operated vs. nonoperated mutation carriers Reported variables Study population Prophylactic hysterectomy Nonoperated (N = 24)p value a b (N = 76) performed (N = 42) n (%) n (%) n(%) 1. Parity: 1 or more deliveries 66 (86.8) 37 (88.1) 21 (87.5) 1.000 2. Own health considered intermediate or good 50 (65.8) 24 (58.5) 18 (75.0) 0.282 3. In a relationship at mutation diagnosis 67 (88.2) 40 (95.2) 19 (79.2) 0.089 4. Attended gynecological appointments regularly 68 (89.5) 37 (88.1) 21 (87.5) 1.000 5. Cancer other than gynecological cancer in family 73 (96.0) 39 (92.9) 24 (100.0) 0.295 6. Family member died of gynecological cancer 17 (22.3) 12 (29.3) 4 (16.7) 0.373 7. Poor tolerance of feeling of insecurity 13 (17.1) 5 (11.9) 5 (20.8) 0.477 8. Strong fear of cancer 32 (42.1) 19 (45.2) 10 (41.7) 0.803 9. Strong fear of surgery/operations 12 (15.7) 6 (14.3) 4 (16.7) 1.000 10. Experience of surgery as responsibility 16 (21.0) 12 (29.3) 3 (12.5) 0.142 11. Feels/has felt pressure for surgery 20 (26.3) 14 (35.9) 5 (22.7) 0.391 12. Satisfied with information and advice in general 43 (56.6) 30 (73.2) 7 (31.8) 0.003 13. Satisfied with information on possible postoperative disadvantages a. Urinary complaints 18 (23.6) 11 (28.9) 2 (9.1) 0.106 b. Chronic pelvic pain 20 (26.3) 12 (31.6) 3 (13.6) 0.215 c. GI-tract complaints 19 (25.0) 12 (31.6) 2 (9.1) 0.061 d. Pelvic prolapses 19 (25.0) 12 (31.6) 2 (9.1) 0.061 d d d 14. Endometrial biopsy pain (NRS score) (N = 54) (N = 28) (N = 19) a. 0–5 39 (72.2) 21 (75.0) 11 (57.9) b. 6–10 15 (27.8) 7 (25.0) 8 (42.1) 0.339 15. Median age, years Year (range) Year (range) Year (range) a. At mutation testing 35.2 (22–65) 42.3 (25–65) 31.6 (22–48) < 0.001 b. At survey 48.8 (30–76) 56.9 (43–72) 43.2 (30–76) < 0.001 Defined by study questionnaire responders 10 subjects with nonprophylactic hysterectomy excluded from comparison Comparison between nonoperated and prophylactically operated subjects Total of 54 subjects answered this question (22 subjects did not respond) 1 3 Factors associated with decision-making on prophylactic hysterectomy and attitudes towards… 181 to this question. The median NRS among Women with LS not a significant factor for decision-making, at least in our was 3.5. Most women (72.2%) reported mild or intermedi- study population. The association of older age at mutation ate pain associated with endometrial biopsy measured by testing and at survey was expected since all recommenda- NRS (NRS 0–5), and strong pain (NRS 6–10) was reported tions for the initiation of surveillance and the timing of pro- by 27.8% of women. Approximately 40% of participants phylactic surgery are age-dependent. reported pain to be very mild or there was no pain at all The majority of subjects considered gynecological sur- (NRS 0 to 2). Pain levels during endometrial biopsy did veillance to be beneficial in general. There have been some not influence the rate of prophylactic surgeries when ana- previous qualitative studies on the topic showing experi- lyzed either as a continuous variable or when categorized. enced benefit [8, 10]. We show that some of the study Regardless of the history of prophylactic hysterectomy, a subjects reported being either inadequately or not at all majority of women (43/76; 59.7%) reported satisfaction informed about the risks and possible long-term side effects with the information and advice regarding LS in general and of prophylactic surgery. Earlier qualitative studies evaluat- prophylactic surgery provided by gynecologists. Only four ing surgery decisions have reported similar results: muta- subjects did not answer this question. The self-reported sat- tion carriers are mainly satisfied with prophylactic surgery isfaction with general LS-associated information and advice decisions, but nonoperated women are not completely satis- by experts was dependent on the history of prophylactic fied with the information they receive [6 , 8]. One possible hysterectomy: 73.2% of the operated patients were satisfied explanation for this is that more detailed surgery-related versus only 31.8% of the nonoperated patients (p = 0.003; information is provided only when the decision to undergo Table 3). The compliance rate with gynecological surveil- surgery has been made. From this retrospective analysis, it lance was similar among operated and nonoperated women is not possible to draw straightforward conclusions, but it is (88.1% versus 87.5%, respectively, p = 1.00; Table 3). probable that women with LS may warrant more detailed In addition, there was a trend for women who chose pro- and structured information on surgery during surveillance. phylactic hysterectomy to have received more information Some of our study subjects were not satisfied with the on certain postoperative complications than women who had surveillance protocol. A few LS carriers reported not being not chosen surgery yet (p = 0.061 for information on GI-tract informed at all about gynecological surveillance appoint- postoperative complications and pelvic prolapses; Table 3). ments. This probably influenced their decision-making on prophylactic surgery and may have led them to refuse it, thus keeping them susceptible to EC. This finding emphasizes the Discussion importance of structured national guidelines for the manage- ment of LS. In this study, LS pathogenic variant carriers’ attitudes The strengths of our study include a well-defined popula- towards gynecological surveillance and satisfaction with tion of women with LS who were all verified as germline the advice and information provided by experts were sig- pathogenic variant carriers and were not just women who nificantly associated with having had prophylactic surgery. had a strong family history of EC or CRC. The study cohort To our knowledge, this finding highlights the importance of identified from the LSRFi included 112 women, and the general information in this context and emphasizes the role response rate was quite high (68%), which is in line with of attending medical staff. On the other hand, compliance previous questionnaire-based studies among subjects with with surveillance was similar between prophylactically oper- a hereditary cancer predisposition [14, 15]. ated and nonoperated women, suggesting that the quality of There are some limitations to our study. The setting is ret- information may play a significant role in decision-making. rospective, and a questionnaire survey is subject to the risk Parity and experienced pain during endometrial sampling of misremembering background factors. This misremember- did not correlate with the decision to undergo prophylactic ing may therefore cause recall bias. However, we consider surgery. A previous study indicated that parity influences that a questionnaire-based survey is also a valuable method decision-making, but the data were derived from a very to collect the points of view and experiences of women with small study population of ten women with LS [8]. Severe LS. Prophylactically operated subjects were expectedly sig- pain experienced during endometrial sampling has been pre- nificantly older at the time of mutation diagnosis and at viously shown to be the main reason to quit screening, thus study than nonoperated women, which can also cause some possibly lowering the threshold for surgery [10]. Different bias. A comparison of responders to nonresponders did not populations may explain differences in the results concern- reveal any major concerns other than the slightly more fre- ing the experience of pain during endometrial sampling. quent rate of prophylactic hysterectomy among the respond- Since ultrasound examination is not sufficient as a single ers, which may cause potential bias and must be taken into surveillance method in terms of EC prevention, [16] it is a account when interpreting the present results. Some of relief that pain associated with endometrial sampling was the study subjects had a hysterectomy for nonprophylactic 1 3 182 M. H. Kalamo et al. 4. Herzig DO et al (2017) Clinical practice guidelines for the surgi- reasons, and they had to be excluded from the analyses when cal treatment of patients with lynch syndrome. Dis Colon Rectum estimating the factors influencing the decision-making about 60(2):137–143 prophylactic surgery. 5. Møller P et al (2017) Cancer incidence and survival in Lynch In conclusion, we show here new descriptive data on the syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome attitudes towards surveillance and factors associated with the database. Gut 66(3):464–472 history of prophylactic surgery in a Finnish cohort of women 6. Schmeler KM et al (2006) Prophylactic surgery to reduce the risk with LS. Based on our results, surveillance is well accepted. of gynecologic cancers in the Lynch syndrome. N Engl J Med Considering the results of our study, we suggest that the 354(3):261–269 7. Nyström-Lahti M et  al (1995) Founding mutations and alu- mutation carriers should be systematically informed about mediated recombination in hereditary colon cancer. Nat Med surveillance and its aims and about prophylactic surgery. We 1(11):1203–1206 suggest that information should be offered regardless of the 8. Etchegary H, Dicks E, Watkins K, Alani S, Dawson L (2015) timing of the prophylactic surgery. Decisions about prophylactic gynecologic surgery: a qualitative study of the experience of female Lynch syndrome mutation car- riers. Hered Cancer Clin Pract 13(1):10 9. Etchegary H, Dicks E, Tamutis L, Dawson L (2018) Quality of Funding Pirkanmaa Hospital District’s Research Funding, Cancer life following prophylactic gynecological surgery: experiences of Society of Finland. female Lynch mutation carriers. Fam Cancer 17(1):53–61 10. Helder-Woolderink J, de Bock G, Hollema H, van Oven M, Mour- Compliance with ethical standards its M (2017) Pain evaluation during gynaecological surveillance in women with Lynch syndrome. Fam Cancer 16(2):205–210 11. 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