Untersuchung der Mikrosatelliteninstabilität beim kolorektalen Karzinom

Zusammenfassung

Einleitung: Mit etwa 3−5 % aller kolorektalen Karzinome (KRK) ist das Lynch-Syndrom (LS) die häufigste erbliche Ursache dieser Erkrankung. Zugrundeliegend ist ein autosomal-dominanter Erbgang mit hoher Penetranz. Im klinischen Alltag wird die zugrundeliegende Disposition leider häufig nicht als solche erkannt.

Methoden: Anhand der Literatur werden Strategien zur Identifikation von LS-Patienten vorgestellt und kritisch diskutiert. Ziel ist es, mit einem Algorithmus dem Kliniker einen Leitfaden zur Erkennung dieser durch multiple Karzinomerkrankungen gefährdeten Patienten an die Hand zu geben.

Ergebnisse: Die Erhebung der Familienanamnese und Anwendung der revidierten Bethesda-Kriterien und Amsterdam-II-Kriterien legt in vielen Fällen den Verdacht auf ein LS nahe, was sich durch immunohistochemische Untersuchungen, Bestimmung der Mikrosatelliteninstabilität und zuletzt dem Mutationsnachweis durch Gensequenzierung bestätigen lässt.

Diskussion: Bei strikter Anwendung der revidierten Bethesda-Kriterien werden 12−28 % der LS-Patienten nicht als solche erkannt, sodass durch Experten bereits eine immunohistochemische Untersuchung bei allen KRK-Patienten unter 70 Jahren gefordert wird. Bei Diagnosestellung eines KRK sollte die Disposition vor Durchführung des erforderlichen Eingriffs abgeklärt werden, um Patienten in die Entscheidungsoption einer prophylaktisch erweiterten Resektion einzubeziehen. Bei postmenopausalen Frauen ist die Option einer Hysterektomie bzw. auch Salpingoophorektomie anzusprechen, da sie durch die Leitlinien empfohlen wird. Da Patienten und betroffene Angehörige einer intensiven Vor- bzw. Nachsorge bedürfen und auch erweiterte chirurgische Maßnahmen zur Prophylaxe von Karzinomen auch anderer Organe mit Mutationsträgern besprochen werden müssen, ist eine frühzeitige Identifikation der zugrundeliegenden familieneigenen Mutation von eminenter Wichtigkeit.

Schlussfolgerung: Die Möglichkeiten, Patienten mit LS durch pathologische Untersuchungen zu identifizieren, sind exzellent. In der klinischen Praxis scheitert die Erkennung der Betroffenen allerdings leider häufig an Basisuntersuchungen wie der Erhebung der Familienanamnese und einer nicht vorhandenen Awareness.

Summary

Introduction: Lynch Syndrome is the most common cause or hereditary colorectal cancer (CRC), accounting for 3−5 % of all CRC, following an autosomal dominant mode of inheritance. The clinical phenotype is characterized predominantly by colorectal and endometrial cancers, the underlying cause being a deficiency in the mismatch repair system. In clinical practice, Lynch syndrome patients are widely underdiagnosed.

Methods: A literature review revealing different strategies efficient in identifying Lynch syndrome were analyzed and evaluated. Paramount for the identification of the hereditary condition still remains the ascertainment of family history, followed by examination of a mismatch repair deficiency via immunohistochemistry and/or microsatellite instability. Mutation analysis vie sequencing allows confirmation of the hereditary cause and is the prerequisite for predictive testing of at-risk relatives.

Results: Fulfilment of one of the revised Bethesda criteria as the trigger to perform immunohistochemical staining or PCR-based microsatellite analysis is broadly acknowledged and recommended. However, stringent application of the Bethesda criteria will miss 12−28 % of the affected patients. Therefore many experts today recommend unselected screening for Lynch syndrome in every patient with a colorectal cancer before the age of 70 (Jerusalem recommendations). In the light of surgical decision-making at the time of a colorectal cancer, we propose that preoperative testing should be advised. We here present an algorithm in accordance to the guidelines with the difference, that this analysis should be triggered preoperatively − at least in patients fulfilling the Bethesda criteria.

Conclusion: The methods to identify Lynch syndrome patients are excellent. More awareness is urgently needed to identify affected persons. The therapeutical options such as extended surgery and/or prophylactic hysterectomy with/without bilateral salpingoophorectomy should be discussed at the time of the colorectal primary and therefore established in the preoperative setting. For this, excellent collaboration between gastroenterologists, pathologists and surgeons is mandatory.

Schlüsselwörter

Kolorektales Karzinom - Lynch-Syndrom - HNPCC - Mikrosatelliteninstabilität - Immunohistochemie

Keywords

colorectal cancer - Lynch Syndrom - HNPCC - microsatellite instability - immunohistochemistry

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