Das Lynch-Syndrom – Epidemiologie, Klinik, Genetik, Screening, Therapie

Zusammenfassung

Das Lynch-Syndrom ist charakterisiert durch ein familiär gehäuftes Auftreten von kolorektalen Karzinomen und Endometriumkarzinomen in Verbindung mit verschiedenen anderen Karzinomen. Der zugrunde liegende Erbgang ist autosomal-dominant und zeigt eine Penetranz von 85 − 90 %. Molekulargenetisch handelt es sich um eine Mutation in einem der Mismatch-Reparatur-Gene. Die Kenntnis der molekulargenetischen Grundlagen des Lynch-Syndroms ermöglichen die Durchführung einer gezielten prädiktiven Diagnostik in Familien mit nachgewiesener Mutation. Voraussetzung zum Erkennen von Patienten mit Lynch-Syndrom ist die Kenntnis der klinischen und histopathologischen Besonderheiten dieser Erkrankung. Typisch für Indexpersonen mit einem Lynch-Syndrom ist das frühe Erkrankungsalter von etwa 45 Jahren sowie eine charakteristische Lokalisation im rechten Hemikolon. Um die Identifikation des weitläufig übersehenen Syndroms zu verbessern, muss das Augenmerk des Klinikers heute weit über diesen „klassischen“ Phänotyp hinaus reichen. Hierzu müssen fast alle Disziplinen in der Medizin aufgefordert werden! Histopathologisch finden sich in den oft gering differenzierten Karzinomen gehäuft solide Areale ohne tubuläre Anordnung und in der Peripherie „Crohn’s-like lesions“, peritumoröse oder tumorinfiltrierende Lymphozyten. Im Rahmen der klinischen Evaluierung von Karzinompatienten kommt der Erhebung einer umfassenden Familienanamnese und der Abgleich derselben mit den Amsterdam-I- und -II- sowie den revidierten Bethesda-Kriterien eine große Bedeutung zu. Bei Vorliegen der Kriterien sollte eine Mikrosatellitenanalyse und bei nachgewiesener Mikrosatelliteninstabilität nach einem humangenetischen Beratungsgespräch eine molekulargenetische Analyse des entsprechenden Mismatch-Reparatur-Gens erfolgen. Patienten mit nachgewiesener Mutation und Hochrisikopersonen aus Familien, in denen die krankheitsverursachende Mutation nicht identifiziert werden konnte, sollten an jährlichen Früherkennungsuntersuchungen teilnehmen. Aufgrund der inkompletten Penetranz der Mutation gibt es keine Empfehlung zur rein prophylaktischen Chirurgie bei Patienten ohne Karzinomnachweis. Inwieweit eine prophylaktische Erweiterung der onkologischen Resektion eines kolorektalen Karzinoms oder eine prophylaktische Hysterektomie für Lebensqualität und Überleben von Vorteil sein könnte, ist bislang ungeklärt.

Abstract

Lynch syndrome is characterised by a familial predisposition of colorectal and endometrial carcinomas in association with a variety of other cancers. The underlying autosomal dominant inheritance has a penetrance of 85 − 90 %. The molecular genetic underlying mechanism is a mutation in one of the mismatch-repair genes. The identification of the molecular genetic basis of Lynch syndrome enabled the implementation of predictive testing in families with a proven mutation. A prerequisite to detect patients with Lynch syndrome is a knowledge of the clinical and histopathological features of this disease. Typical for Lynch syndrome associated carcinomas is the early age of onset of about 45 years as well as the characteristic localisation within the right hemicolon. However, in order to increase the rate of identification of this underestimated syndrome, the awareness of the clinician must extend beyond this classical phenotype. For this purpose close interdisciplinary cooperation is warranted! The cancers are mostly low-differentiated with solid areas without a tubular structure. Crohn’s-like lesions as well as peritumoural and tumour-infiltrating lymphocytes may frequently be found in the periphery of the malignant formation. Within the framework of the clinical evaluation of any index patient, an extended family history must be ascertained and matched with the Amsterdam-I and -II criteria as well as with the revised Bethesda criteria. If a patient fulfills these criteria, testing for microsatellite instability and if positive after genetic counselling mutation analysis should be recommended. Patients with a proven mutation and high risk individuals from families with an unidentified underlying mutation are encouraged to participate in an intensified screening programme. Due to the incomplete penetrance there is no recommendation towards prophylactic surgery in high-risk individuals without tumour manifestation. Nevertheless, the effect on quality of life of prophylactic, extended surgery in addition to the obligatory oncologic resection with or without prophylactic hysterectomy needs to be established in prospective controlled trials.

Schlüsselwörter

hereditäres nicht polypöses kolorektales Karzinom - HNPCC - Lynch-Syndrom - familiär kolorektales Karzinom - Screening - Prävention

Key words

hereditary non-polyposis colorectal cancer - HNPCC - Lynch syndrome - familiar colon cancer - screening - prevention

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