O R I G I N A L A R T I C L E
Value-based healthcare in Lynch syndrome
Simone D. Hennink•Nandy Hofland•Jessica P. Gopie •Corinne van der Kaa• Kimberley de Koning• Maartje Nielsen•Carli Tops•Hans Morreau•
Wouter H. de Vos tot Nederveen Cappel• Alexandra M. J. Langers• James C. Hardwick•Katja N. Gaarenstroom •Rob A. Tollenaar•
Roeland A. Veenendaal•Aad Tibben• Juul Wijnen•Magdalena van Heck • Christi van Asperen•Anne J. Roukema•Daan W. Hommes•Frederik J. Hes • Hans F. A. Vasen
ÓSpringer Science+Business Media Dordrecht 2013
Abstract Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC), is caused by a defect in one of the mismatch repair (MMR) genes. Car-riers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. Over the last few years, value-based healthcare has been introduced as an approach to the cost-effective delivery of measurable patient value over complete cycles of care. This requires all involved stakeholders to formulate and validate ‘patient value’ for Lynch syndrome, as well as to identify targets and associated costs. The aim of this study was to develop a value-based care model for Lynch syndrome that can determine patient value and associated costs, and to design
a coordinated care pathway from existing guidelines. All specialists in our hospital involved in the management of LS patients evaluated the care delivered to these patients at their department and formulated outcome measures rele-vant to patient value. Patients were then invited to com-plete a questionnaire that assessed the importance of these measures on a scale of 1–10. Six high-value outcomes were identified: (1) prevention of cancer or detection of early stage cancer (2) rapid results from MMR gene mutation testing (3) rapid investigation of the colon and uterus (4) no/little pain during colonoscopy and gynaecologic exam-ination/biopsy (5) the offer of psychological help and (6) registration with the Dutch Lynch syndrome registry. A S. D. HenninkA. M. J. LangersJ. C. Hardwick
R. A. Veenendaal
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands N. HoflandJ. P. GopieM. NielsenC. TopsA. Tibben J. WijnenC. van AsperenF. J. Hes
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
C. van der KaaK. de KoningM. van Heck A. J. RoukemaH. F. A. Vasen
Dutch Lynch Syndrome Registry, Netherlands Foundation for the Detection of Hereditary Tumors, Leiden, The Netherlands H. Morreau
Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
W. H. de Vos tot Nederveen Cappel
Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands
K. N. Gaarenstroom
Department of Gynaecology, Leiden University Medical Centre, Leiden, The Netherlands
R. A. Tollenaar
Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands
A. J. Roukema
Department of Surgery, St Elisabeth Hospital, Tilburg, The Netherlands
D. W. Hommes
Division of Digestive Diseases, University of California, Los Angeles, CA, USA
H. F. A. Vasen (&)
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
e-mail: hfavasen@stoet.nl DOI 10.1007/s10689-013-9655-6
total of 38 (59 %) out of 62 patients completed the ques-tionnaire. The relevance of all outcomes was confirmed by the patients and mean scores varied from 7.2 to 9.9. Patients underscored the relevance of both proper patient education and the efficiency of surveillance during their care cycle. Value-based care delivery for Lynch syndrome includes the implementation of six parameters related to prevention and early detection of cancer, a short cycle time and registration to ensure continuation of care. Estimated costs are€3320 for the first cycle of care (€3550 including gynaecologic surveillance) and approximately 720 per subsequent annual cycle (€ 950 including gynaecologic surveillance).
Keywords Lynch syndrome Colorectal cancer Endometrial cancerPreventionValue-based health care Patient valueOutcome measuresLynch syndrome registry
Introduction
Lynch syndrome (LS), previously referred to as hereditary non-polyposis colorectal cancer (HNPCC), is one of the most frequent forms of hereditary colorectal cancer (CRC), accounting for approximately 1–3 % of all CRC cases [1]. LS is caused by a defect in one of the mismatch repair (MMR) genes, MSH2, MLH1, MSH6 or PMS2, and is characterized by a very high risk for CRC (25–70 %), endometrial cancer (30–70 %) and other cancers (\20 %) [2]. A hallmark of the disease is the presence in tumours of microsatellite instability (MSI). The primary clinical fea-tures are an early age at onset and a high risk of developing multiple tumours. The identification of individuals at risk of LS is important, as studies have shown that colonoscopic surveillance allows early detection of tumours which leads to an improvement in prognosis [3].
Over the last few years a new comprehensive approach to care has been proposed that aims to achieve high value for patients defined as outcome relative to costs [4]. A major advantage of this type of approach is that it covers the complete cycle of care for a specific condition, starting from the first complaints, via diagnosis and treatment, and on to recovery; or in the case of LS, starting from the moment of referral to a Clinical Genetics Centre, via confirmation/exclusion of LS, to a surveillance program. All disciplines involved in the care of a patient have an equally important contribution to make and are therefore equally accountable for the final outcome.
In this approach, patient value can be created over the full cycle of care and should be defined by the needs of the client. Insight into the costs of care delivery at the various stages makes it possible to evaluate whether an outcome
improves when available finances are redistributed amongst the various services of the total care [4].
Value is often revealed over time and is manifested in long-term outcomes such as the prevention of CRC by ongoing surveillance colonoscopies in Lynch syndrome. The only effective way to accurately measure value is to track patient outcomes longitudinally.
The aim of the present study was to develop a similarly comprehensive approach for patients suspect for LS in our hospital. The first step was to evaluate LS patient care at the various departments. We then established relevant outcomes for these individuals. Finally, we evaluated whether these outcomes were indeed relevant by conduct-ing a survey amongst LS patients.
Methods
Evaluation of the care delivered to Lynch syndrome patients
The Department of Gastroenterology and the Department of Clinical Genetics of the Leiden University Medical Centre (LUMC) both have a 30-year history of care for patients with hereditary CRC syndromes, including LS and familial adenomatous polyposis.
Currently, most patients seen at the Department of Clinical Genetics with an increased risk of developing CRC are referred by general practitioners. A second group consists of patients who have recently been diagnosed with early onset or multiple CRC at the Departments of Gas-troenterology and/or Surgery. A third group of referrals are patients undergoing colonoscopy, with a known high risk due to a strong family history of CRC. The final group consists of patients with a relative who tested positive for a MMR gene mutation. The main referral route is shown schematically in Fig.1. Specialists involved in the care of individuals suspected for LS include genetic counsellors, pathologists, clinical (molecular) geneticists, psycholo-gists, gastroenterolopsycholo-gists, gynaecolopsycholo-gists, surgeons and registry workers.
During 2012, these specialists carried out an evaluation of current activities at each stage in the care of LS patients and then discussed which outcome measures might be relevant to the patients.
Survey of Lynch syndrome patients
LS patients consecutively diagnosed at the LUMC were selected from the LS database of the Dutch Lynch syn-drome registry. In order to obtain a population of patients who all went through the same cycle of care, only those with a confirmed MMR gene mutation were included.
Sixty-four patients were identified. These patients were invited to participate in this survey and to complete a questionnaire that assessed the importance of the outcomes (on a scale 1–10) in the cycle of care identified by the specialists. In addition, patients were invited to formulate their own outcomes.
Results
Evaluation of care at each department
A short description of the care delivered at each department and the time needed for each activity is provided below. An overview of the full cycle of care for patients suspect for LS is shown in Fig.1.
Diagnosis of Lynch syndrome (LS): Department of Clinical Genetics and Pathology
The average referral time for consultation at the Depart-ment of Clinical Genetics is two weeks. In this time, the counselees are requested to complete a family history questionnaire. The reason for referral is discussed during the first visit. A detailed family history of cancer occur-rence is taken, including type of cancer and age at diag-nosis. Using this information, a three-generation pedigree
is constructed. If there is sufficient suspicion for LS, the patient will be informed of the need for additional analysis for colorectal tumours (or other tumours), i.e. testing of MMR-deficiency by MSI and IHC (immunohistochemical) analysis. In cases where the counselee does not have CRC, he or she will be asked to approach relatives in order to obtain informed consent for analysis of their tumours and collection of their medical and pathology reports, with the aim of confirming suspect LS. In addition, the counselees are informed of the possible outcomes of the genetic analyses and the options for surveillance. They are also provided with information on the national registry and are given a patient information pamphlet. Collecting informed consent, medical information and tumour tissue (of rela-tives) generally requires 2–4 weeks. The process of MSI and IHC analyses generally requires another 2 weeks.
On the second visit, the outcomes of all retrieved medical information and tests are discussed. If the molec-ular analysis of the tumour does not suggest LS (micro-satellite-stable tumours and normal expression of the MMR proteins), the patients are reassured that Lynch syndrome can be excluded with high confidence. Recommendations for colonoscopic surveillance are given based on the family history for CRC. However, since there is a chance that a phenocopy has been tested, testing of a second tumour must be considered. If the tumour analysis provides evi-dence for LS, then the option of DNA analysis for detection Fig. 1 An overview of the full cycle of care of patients suspect for Lynch syndrome
of the causative germline MMR defect is discussed. If a patient has problems taking decisions, the patient is refer-red to a psychologist. Subsequently, blood samples are taken from either, (1) an index patient with CRC displaying MMR deficiency, (2) a relative with CRC displaying MMR deficiency or (3) if no relatives with CRC are alive, mul-tiple healthy first-degree relatives. On the basis of the results of IHC analysis it is usually possible to restrict the mutation analysis to one gene; the evaluation of one MMR gene requires 8 weeks.
During thethirdvisit, the results of the germline mutation analysis are discussed. In cases where a germline MMR mutation is identified the consequences are again discussed, including the increased lifetime risks of developing certain types of cancer and the options for surveillance or surgery. Patients are then referred to a gastroenterologist and gynaecologist for surveillance. The average referral times for consultation at the Gastroenterology and Gynaecology Departments are 8 and 4–6 weeks, respectively. All patients are invited to express their feelings regarding the outcome of the test and to indicate whether they need the support of a psychologist or social worker. Information is also provided about the existence and aims of a national registry for Lynch syndrome patients.
In addition, the importance of informing other family members about the hereditary condition and the possibility of genetic testing are discussed. Patients are usually asked to distribute a letter, containing all relevant information, among family members. Help in distributing this infor-mation is also offered.
Finally, the counselee receives a letter that summarizes all that has been discussed in the three visits, including general information on Lynch syndrome and guidelines for surveillance.
Surveillance (CRC): Department of Gastroenterology and Hepatology
On thefirst visit, the indications for colonoscopy and the effectiveness of colonoscopic surveillance are discussed with the patient. Five to ten per cent of LS patients may develop CRC (85 % at an early stage) over a period of ten years, despite intensive surveillance [5]. Following Lynch syndrome protocol, the recommendations in cases of a proven MMR gene mutation are for a colonoscopy every 1–2 years, starting at the age of 25 [5]. Other issues that are discussed are the preparation of the bowel, the possibility of sedation and/or pain reducing drugs and the procedure of colonoscopy itself, including possible complications. The usual waiting period for colonoscopy is 4–6 weeks.
Colonoscopy is performed on the second visit. The outcome is discussed directly after the investigation. If a CRC is suspected, a nurse practitioner will guide the
patient during dissemination examinations, immediately following on from the colonoscopy. If the cancer is con-firmed, the option of more extensive surgery (subtotal colectomy) will be discussed. The patient will undergo surgery within 5–10 working days.
For the remaining patients, the outcome of colonoscopy is discussed during the third visit, including results of pathology examinations when available.
If the patient is registered with the Dutch Lynch syn-drome registry, the results of the colonoscopy will be submitted to the registry, but if the patient is not yet reg-istered, the gastroenterologist will discuss its importance. A follow-up colonoscopy is scheduled within 1–2 years. All patients are invited to discuss how they are coping with the knowledge of being at-risk and with the need for bur-densome, lifelong surveillance examinations. If there is evidence for increased psychological distress, help via a psychologist or social worker is offered.
Surveillance (EC): Department of Gynaecology
On thefirstvisit, the gynaecologist discusses the option of surveillance. This commences at the age of 35, by annual transvaginal ultrasound (by indication, followed by pipelle curettage for endometrial biopsy) and CA-125 measure-ments for endometrial and ovarian cancer, and aims to detect the cancer at an early stage. Information on the effectiveness of gynaecologic surveillance is also provided. This is important because, thus far, there is no evidence that screening results in a significant shift to earlier stages of endometrial or ovarian cancer and improved prognosis [6]. In individuals older than 40 years who have completed their family, the option of prophylactic hysterectomy and bilateral salpingo-oophorectomy is discussed. The patient will be informed about the procedures, the burden of the investigations/surgery and possible complications. Pros and cons of the different options are also discussed. The usual waiting time for a transvaginal ultrasound (with or without pipelle curettage) is 4 weeks.
Gynaecologic examination is performed during the sec-ond visit. The patient is informed of the outcome directly following the examination. If pipelle curettage is performed, the results of the pathology examinations are discussed during the follow-up visit. The results of the surveillance examination are submitted to the Dutch Lynch syndrome registry. A follow-up examination, i.e. transvaginal ultra-sound and CA-125 measurement, is scheduled every year. Registration at the Dutch Lynch syndrome registry On completion of the counselling process at the Depart-ment of Clinical Genetics, the carriers of an MMR gene mutation are invited to register with the Dutch Lynch
syndrome registry. The aims of this registry are (1) to improve care for LS patients (2) to evaluate the effec-tiveness of long-term surveillance, and (3) to guarantee the continuity of lifelong surveillance. At regular intervals, the registry sends reminders to specialists to inform them that a surveillance moment is pending.
Outcomes relevant to patients
The specialists identified six outcomes that they considered important for patients: (1) prevention of cancer or detection of early stage cancer (2) rapid results from MMR gene mutation testing (3) rapid investigation of the colon and uterus (4) no/little pain during colonoscopy and gynaeco-logic examination/biopsy (5) the offer of psychogynaeco-logical help, and (6) registration with the Dutch Lynch syndrome registry.
Survey among Lynch syndrome patients
The questionnaire was sent to 64 LS patients and a response was received from 38 patients (59 %). The selected outcomes and the scores are listed in Table1. The relevance of all outcomes was confirmed by the survey. The prevention of cancer (1) CRC and (2) EC in women, was of overriding importance to most patients (scored 9.9).
Another critical outcome for patients was cycle time. A rapid diagnosis, including diagnosis based on MSI/IHC-analyses (3) and DNA mutation analysis (4) or rapid investigation of the colon and uterus (5) scored 9.3 and 9.4, respectively.
A third relevant outcome was discomfort associated with the surveillance examinations [7], which scored 8.5. Patients scored offers of help by a psychologist or social worker at 7.2. Finally, the possibility of registration with the Dutch Lynch syndrome registry was scored at 8.8.
Outcomes suggested by the patients themselves are also shown in Table1. Information about the colonoscopy procedure, bowel preparation and logistics was considered important, and was reported by 21 % of patients (scored 9), followed by information regarding developments in LS research (reported by 24 %, scored 9.0) and full and ade-quate information on LS (reported by 11 %, scored 9.3).
Discussion
Porter has recently argued that achieving high value for patients should be the overarching goal of health care delivery, with value defined as the health outcome achieved per dollar spent [4]. This issue is central for patients and units all actors in the system including payers, Table 1 Outcomes for individuals at risk for Lynch syndrome; 38 of 64 (59 %) patients responded to the questionnaire
Outcome measures Mean (relative)
importance (1-10) Low risk of developing cancer under surveillance Colorectal cancer 9.9
Endometrial cancer
Short time needed for diagnosis and surveillance Pedigree analysis, verification and MSI/IHC analysis 9.3 DNA mutation analysis
referral to gastroenterologist/colonoscopy 9.4 referral to gynaecologist/pipelle-curettage/transvaginal
ultrasound
Providing outcome of surveillance
No or little discomfort during surveillance Colonoscopy 8.5
Transvaginal ultrasound/pipelle curettage
No or little psychological distress After genetic results 7.2 During long-term surveillance
Registered with the Dutch Lynch syndrome registry Guarantee of continuity of surveillance 8.8 Evaluation of surveillance
Outcomes reported by patients Absolute number of patients who reported, and percentage (%)
Mean (relative) importance (1–10)
Providing full and adequate information about LS 4 (11) 9.3
Information about developments in LS research 9 (24) 9.0
Information/bowel preparation/logistics concerning colonoscopy 8 (21) 9.0
Optimal surveillance interval colonoscopy 2 (5) 8.5
providers and suppliers. Measuring, reporting and com-paring outcomes are perhaps the most important steps toward rapidly improving outcomes and making effective choices when reducing costs.
Outcomes should always be defined in relation to the client and should be differentiated from the parameters measuring the process of care. Thus, the crucial factor is this patient-centred approach rather than the care process itself. An appropriate unit for measuring value should encompass all services or activities that jointly determine success in meeting a set of patient needs. This means that outcomes are created by efforts over the full cycle of care. The benefit of any intervention depends on the effective-ness of all other interventions, in contrast with the current situation in which specialists only measure what they themselves control. In this new strategy the contribution of all involved specialists is equally important to the final outcome [4].
In the present study, we first made an inventory of the care currently delivered to patients suspected of LS at the Leiden University Medical Centre (LUMC). A discussion was initiated among the specialists involved in the man-agement of these patients on which outcome measures are relevant to patients and how care in our hospital could be improved through the implementation of these measures. LS patients were then invited to complete a questionnaire that assessed the importance of these outcomes.
One of the most important outcomes was prevention of CRC and endometrial cancer. It is well known that LS patients may develop CRC even when under intensive surveillance; the cumulative reported risk of developing CRC while under surveillance is between 5 and 10 % over a period of 10 years or 20–30 % by the age of 60 years [7– 9]. In order to decrease the number of these ‘interval
CRCs’, a special, dedicated endoscopy programme for LS patients should be implemented, including high quality colonoscopies and the use of chromoendoscopy or other techniques. Unfortunately, the effectiveness of surveillance for endometrial and ovarian cancer is still unknown [5]. However, most screen-detected cases of endometrial can-cer (and ovarian cancan-cer) are diagnosed at an early stage [6]. In order to evaluate the longitudinal effect of LS patient care (i.e. the effectiveness of surveillance), the patients should be registered with the Dutch Lynch syndrome reg-istry. To monitor the outcome of prevention of CRC and endometrial cancer, we will measure the rate of interval carcinomas per six years using data from the registry.
An important factor highlighted in our survey was rapidity of diagnosis and surveillance examinations. The evaluation showed that the cycle time can be substantially shortened, especially the time needed to perform DNA mutation analysis. We just started with performing genetic analyses consecutively in an individual setting (and not in series), which will save time and allow results to be delivered within 4 weeks. Moreover, analysis techniques will develop over time and a Nextgen/whole genome/ whole exon sequencing approach will eventually be implemented in the diagnostics of hereditary CRC, allow-ing multiple genes to be tested simultaneously. However, a disadvantage of this approach is that many gene variants with an as yet unknown clinical significance will be detected.
In addition, the period from the result of the DNA test to the outcome of the surveillance examination can also be shortened. If the clinical geneticist already concludes that a colonoscopy is indicated on the first visit, he/she can directly refer the patient to the gastroenterologist for colonoscopy, saving at least 8 weeks waiting time. The
Table 2 Summary of measurement of patient outcomes, goals and mode of evaluation
Outcome Measurement Goal Mode of evaluation
Prevention or early diagnosis of CRC/EC*
Proportion of patients with interval-CRC per 6 years
\5 % interval CRC per 6 years
Data collection from National registry every 6 years Proportion of patients with localized
CRC/EC
[85 % CRC stage I/II [85 % EC FIGO stage I/II Short cycle time Time referral–genetic test [80 % total cycle time:
\3 months
Two-yearly evaluation Time genetic test–outcome of
surveillance colonoscopy Little discomfort during
surveillance
VAS** score colonoscopy (1–10) VAS scores\4 Continuous measurement after procedure
VAS score pipelle curettage (1–10) Two-yearly evaluation Option of psychological help Proportion of patients offered help [95 % Two-yearly evaluation Compliance Proportion of compliant patients
(\3 months of scheduled colonoscopy)
[95 % Data collection from National registry every 6 years *ECendometrial cancer, **VASVisual Analogue Scale
outcomes related to cycle time will be measured on a two-yearly basis and will be further improved, when possible.
The third patient outcome with a high score was regis-tration with the Dutch Lynch syndrome registry. One of the most important aims of the Lynch syndrome registry is to guarantee the continuity of long-term surveillance. This is important because studies have reported that LS patients under long-term surveillance show a lack of compliance of between 10 and 30 % [7,10]. The registry sends reminders to specialists, letting them know that a surveillance moment is due. Using the data from the registry, we can monitor the compliance rate at 6-yearly intervals.
Another outcome that was considered important was the physical burden associated with surveillance colonoscop-ies. Studies have shown that a substantial proportion of patients experience considerable pain during endoscopy [11], indicating that more attention should be paid to offering adequate sedation and pain management. Using a pain score, we will measure pain following colonoscopy and pipelle curettage and will take appropriate measures should high scores be seen.
Patients also considered the offer of psychological support to be important. Studies have shown that psycho-logical distress directly following genetic testing occurs in a minority of patients and returns to normal levels within a year [12]. In addition, clinically significant distress was reported in 5–10 % of the patients who underwent long-term surveillance [12]. Special efforts should be made to identify these individuals because they can benefit sub-stantially from the help of a psychologist.
The outcomes suggested by the patients themselves mainly dealt with the need for full information about var-ious aspects of care including bowel preparation and
logistics of colonoscopy, and with information about the syndrome and recent results of research. Patient informa-tion pamphlets that address all these issues will be pre-pared. Table2 provides an overview of all mentioned outcomes and the manner in which they will be evaluated in the coming 6 years. During evaluation, the number of outcomes can be expanded in time.
The current costs for each activity are summarized in Table3. The costs of genealogic studies and genetic testing are one-time costs, whereas the costs of surveillance and the registry are on an annual or bi-annual basis. Estimated costs are€3320 for the first cycle of care (€3550 including gynaecologic surveillance) and approximately 720 per subsequent annual cycle (€ 950 including gynaecologic surveillance). The registry is currently financed by the Ministry of Health, Welfare and Sport (VWS). Because the activities of the registry are part of the cycle of care, in the near future the registry costs (estimated at a relatively low amount of€50 per year per patient) will be included in the costs of surveillance.
A common experience of many physicians specialized in familial cancer is the under diagnosis of LS. This is one of the reasons why screening of all CRC for MMR-defi-ciency is recommended by an increasing number of investigators. If this approach is introduced in clinical practice on a national scale, it is a reasonable expectation that many more individuals will be referred to Clinical Genetic Centres in the coming years due to a suspicion of hereditary CRC based on the identification of an MMR-deficiency in their tumour. The implementation of a new approach, based on high-value for patients, will improve care for these patients and may also serve as a model for other hereditary cancer conditions.
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Costs in Euro MSI-analysis 870 Mutation analysis - 1 gene 770 - 4 genes 3080 Immunohistochemical analysis (four proteins)
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- ultrasound and pipelle curettage 990 Registration with Dutch Lynch
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