Kolorektales Karzinom bei V. a. Lynch-Syndrom: ein interdisziplinärer Algorithmus

 

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Zusammenfassung

Mit etwa 3–5 % aller kolorektalen Karzinome (KRK) ist das Lynch-Syndrom das häufigste hereditäre Prädispositions-Syndrom, bei dem neben kolorektalen Karzinomen gehäuft Endometrium-, Magen-, Ovarial- und Urothelkarzinome, aber auch verschiedene andere Karzinome auftreten. Im klinischen Alltag wird das Lynch-Syndrom oft nicht erkannt und bei Verdacht auf das Vorliegen eines Lynch-Syndroms gibt es viele Unsicherheiten hinsichtlich des korrekten diagnostischen und therapeutischen Vorgehens. Darüber hinaus wird die Beratung in Bezug auf die verschiedenen Therapieoptionen und -empfehlungen – vor allem hinsichtlich einer erweiterten Resektion und der Chemotherapie – als schwierig angesehen. Anhand der Literatur werden Strategien zur Identifikation von Lynch-Syndrom-Patienten vorgestellt und kritisch diskutiert. Ziel ist es, einen interdisziplinär konsentierten Algorithmus zum diagnostischen Vorgehen bei Verdacht auf Lynch-Syndrom aufzuzeigen. Die sich daraus ergebenden Konsequenzen für das operative Vorgehen bei Vorliegen eines Lynch-Syndrom-assoziierten KRK werden diskutiert. Der Verdacht auf ein Lynch-Syndrom kann durch die Erhebung der Familienanamnese und die Anwendung der revidierten Bethesda- und Amsterdam-II-Kriterien gestellt werden. Daran schließen sich immunohistochemische Untersuchungen der Mismatch-Reparatur-Gene, eine BRAF-Untersuchung im Falle eines immunohistochemischen Expressionsverlustes von MLH1, ggf. zusätzlich eine Bestimmung der Mikrosatelliteninstabilität (MSI) und zuletzt der Mutationsnachweis durch Gensequenzierung an. Die Möglichkeiten, Patienten mit Lynch-Syndrom durch pathologische Untersuchungen zu identifizieren, sind exzellent. Diese Untersuchungen sollten allerdings bereits präoperativ zum Zeitpunkt der endoskopischen Diagnosestellung eingeleitet werden, um so die Möglichkeit einer prophylaktisch erweiterten chirurgischen Resektion mit dem Patienten und ggf. eine leitliniengerechte, rein prophylaktische Chirurgie des Uterus und evtl. der Ovarien mit den (postmenopausalen) Patientinnen zusätzlich individuell zu besprechen. In der klinischen Praxis scheitert die Identifikation der Betroffenen allerdings häufig an Basisproblemen wie der Erhebung der Familienanamnese und einer nicht vorhandenen „Awareness“ hinsichtlich des Krankheitsbildes. Wenn daran gedacht wird, erfolgen die empfohlenen MSI-Untersuchungen postoperativ in dem Tumorresektat und Patienten werden in die Überlegungen einer erweiterten prophylaktischen Chirurgie nicht mit einbezogen. Die klinische Erfahrung zeigt, dass die postoperative Analyse von Tumorresektaten hinsichtlich Mikrosatelliteninstabilität – auch bei Erfüllung der Bethesda-Kriterien – häufig nicht erfolgt und bei verdächtigem Befund die empfohlene humangenetische Beratung entweder nicht empfohlen oder nicht umgesetzt wird. Hierdurch wird die Chance einer lebenslangen jährlichen Vorsorge der betroffenen Indexperson verpasst und durchschnittlich 3 Mutationsträger pro Familie verpassen die Möglichkeit, aktiv gegen ihr deutlich erhöhtes Karzinomrisiko vorzugehen.

Abstract

Lynch syndrome is the most frequent hereditary cancer syndrome, accounting for approximately 3–5 % of all colorectal cancers. In addition, it is the most frequent predisposing hereditary cause of endometrial cancer and is also associated with gastric cancer, ovarian cancer, cancer of the urinary tract as well as several other cancers. In clinical practise Lynch syndrome is frequently not detected and many clinicians admit uncertainties regarding diagnostic procedures. Also, counselling of patients is considered difficult regarding therapeutic – especially prophylactic surgical and chemopreventive options and recommendations. Based on a review of available literature we discuss optimized strategies for improved detection of suspected Lynch syndrome patients. The aim of this review is to establish a clinical algorithm of how to proceed on a diagnostic level and to discuss surgical options at the time of a colorectal cancer. In order to identify patients with Lynch syndrome, family history should be ascertained and evaluated in regards to fulfilment of the Amsterdam-II- and/or the revised Bethesda criteria. Subsequently immunohistochemical staining for the mismatch-repair-genes, BRAF testing for MLH1 loss of expression, as well as testing for microsatellite instability in some, followed by genetic counselling and mutation analysis when indicated, is recommended. Pathological identification of suspected Lynch syndrome is readily feasible and straightforward. However, the need of performing these analyses in the tumor biopsy at the time of (gastroenterological) diagnosis of CRC neoplasia is essential, in order to offer patients the option of a prophylactically extended surgery and – as recommended in the German S3 guidelines – to discuss the option of a merely prophylactical hysterectomy and oophorectomy (if postmenopausal) in women. Close cooperation between gastroenterologists, pathologists and surgeons is warranted, so that patients may benefit from options of extended or prophylactically extended surgery at the time of diagnosis of a colorectal primary. Patients nowadays must be involved in informed decision-making regarding prophylactic or extended prophylactic surgery at the time of a colorectal primary. To date, however, limitations in daily clinical practise, the failure to assess family history and the lack of awareness of this important hereditary syndrome is the major asset leading to severe underdiagnosis and putting to risk the indexpatients themselves and their families to (metachronous) CRC and the associated extracolonic cancers. If at all tumors of patients fulfilling Bethesda criteria will be analysed for MSI in the surgical specimen and therefore Lynch syndrome patients are not given the opportunity to opt for extended surgery. In clinical experience the postoperative MSI-analysis is inconsistently performed – even if the Bethesda criteria are fulfilled – and in case of suspected Lynch syndrome genetically counselling is not consistently recommended. Therefore affected cancer patients are left unaware of their increased genetic risk and in average 3 high-risk gene carriers per family miss the opportunity to actively engage in the recommended screening program.

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