Molekulare Pathogenese von Schilddrüsenknoten – Bedeutung für die klinische Versorgung

Zusammenfassung

Schilddrüsenknoten stellen heterogene Tumore dar, mit unterschiedlichen molekularen Signaturen. Während benigne Schilddrüsenknoten poly- oder monoklonalen Tumoren entsprechen, sind Schilddrüsenkarzinome monoklonale und damit „echte“ Neoplasien. Ursächlich für die Neoplasien sind somatische Mutationen, welche zur konstitutiven Aktivierung spezifischer Signalkaskaden führen und den jeweiligen histologischen, teilweise auch den funktionellen Phänotyp des Schilddrüsentumors bestimmen. Eine Dedifferenzierung von Schilddrüsenkarzinomen geht mit dem Auftreten weiterer Mutationen in den Tumoren einher. Die Mutationslast der Schilddrüsenkarzinome korreliert mit deren biologischem Verhalten.

Im klinischen Alltag kann die Kenntnis der ursächlichen somatischen Mutation in der zytologischen Differenzialdiagnose helfen. In der prognostischen Einschätzung von Schilddrüsentumoren hat der Nachweis von klassischen Onkogenmutationen (BRAF, RAS) wenig Relevanz. Andere genetische Veränderungen, insbesondere TERT Promoter Mutationen, die mit zunehmender Häufigkeit in fortgeschrittenen SD-Karzinomen auftreten, haben wahrscheinlich eine prognostische Bedeutung. Von großer Relevanz ist die molekulare Signatur jedoch für die Entwicklung und Anwendung passgenauer „zielgerichteter“ Therapien bei fortgeschrittenen Karzinomen (radioiodrefraktäres DTC, PDTC und ATC, metastasiertes medulläres Karzinom). Hierfür gibt es aus klinischen Studien sowie Einzelfallberichten zunehmend Hinweise, die das Konzept der „Oncogen-Addiction“ als pathogenetisch relevanten Mechanismus der SD-Tumorigenese und Karzinogenese unterstreichen.

Abstract

Thyroid nodules represent heterogeneous tumors with distinct molecular signatures. While benign thyroid nodules correspond to poly- or monoclonal tumors, thyroid carcinomas are monoclonal and thus “real” neoplasms. These are caused by somatic mutations that lead to the constitutive activation of specific signaling cascades and determine the corresponding histology and also partly the functional phenotype of the thyroid tumor. Dedifferentiation of thyroid carcinomas is accompanied by the occurrence of additional mutations in the tumors. The mutation load of thyroid carcinomas correlates with their biological behavior.

In clinical practice, detection of somatic mutations can help in the cytological differential diagnosis. In the prognostic assessment of thyroid tumors, proof of classical oncogene mutations (BRAF, RAS) has little relevance. Other genetic alterations, especially TERT promoter mutations that occur with increasing frequency in advanced thyroid carcinomas, probably have a prognostic significance. The molecular signature, however, is of great relevance for the development and application of targeted therapies in advanced carcinomas (radioactive iodine-refractory DTC, PDTC and ATC, metastatic medullary carcinoma). For this, there is increasing evidence from clinical studies and case reports that underline the concept of “oncogene addiction” as a pathogenetically relevant mechanism of thyroid tumorigenesis and carcinogenesis.

Schlüsselwörter

Schilddrüsenkarzinom - somatische Mutation - TERT Promoter Mutation - molekulare Signatur - Oncogen-Addiction

Key words

thyroid carcinoma - somatic mutation - TERT promoter mutation - molecular signature - oncogene addiction

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