Grundlagen der Tumorentstehung und die Bedeutung Humaner Papillomaviren (HPV) bei Kopf-Hals-Karzinomen

Zusammenfassung

Plattenepithelkarzinome des Kopf-Hals-Bereiches (head and neck squamous cell carcinoma, HNSCC) gehören zu den häufigsten bösartigen Tumorerkrankungen weltweit. Während die Inzidenz von Larynx- und Hypopharynxkarzinomen abnimmt, wird aktuell eine Zunahme bei Oropharynxkarzinomen (oropharyngeal squamous cell carcinoma – OSCC) angenommen. Zigarettenrauchen und Alkoholkonsum sind klassische Risikofaktoren für HNSCC. In den letzten Jahren hat sich gezeigt, dass in einem Prozentsatz zwischen 25 und 60% OSCC mit einer Infektion durch onkogene humane Papillomaviren (HPV) assoziiert sind. Die Entstehung eines Kopf-Hals-Tumors wird normalerweise wesentlich durch Akkumulation genetischer Veränderungen, die zu Inaktivierung von Tumorsuppressorgenen oder Aktivierung von Proto-Onkogenen führen, vorangetrieben. Dabei führt eine mehr oder weniger gleichförmige zeitliche Abfolge von DNA-Schäden zur genetischen Instabilität. Ein häufiges frühes Ereignis ist dabei beispielsweise eine Deletion im kurzen Arm des Chromosoms 9, welche zur Inaktivierung des p16-Gens führt. Bei HPV-induzierter Karzinogene ist dagegen die Expression der viralen Proteine E6 und E7, die zu einer Inaktivierung der zellulären Tumorsuppressorproteine p53 und Rb führen, für die Tumorentstehung entscheidend. Die HPV-Assoziation von HNSCC kann mit in der Routine etablierten Methoden nachgewiesen werden. Der natürliche transorale Infektionsweg ist nicht sicher aufgeklärt. Tatsache ist, dass die perorale HPV-Infektion nicht selten ist, und normalerweise ereignislos abheilt. Rauchen scheint die Wahrscheinlichkeit für die Entwicklung eines HPV-assoziierten Tumors zu begünstigen. Neben bekannten klassischen Prognosefaktoren ist die Aufdeckung einer HPV-Assoziation wegweisend. Die prognostische Relevanz von HPV übersteigt wahrscheinlich viele bekannte Risikofaktoren, beispielsweise eine regionäre Metastasierung. Hierdurch werden sich in Zukunft möglicherweise auch unterschiedliche Therapieansätze für beide Untergruppen von Patienten ergeben. Insbesondere Patienten mit HPV-assoziierten OSCC könnten möglicherweise auch weniger aggressiv erfolgreich behandelt werden. Andere molekulare Marker sind bisher nicht in der Routine etabliert. Abschließend wird im Referat ein Ausblick auf zielgerichtete Therapieansätze gegeben, von denen in der klinischen Praxis bisher lediglich Antikörper gegen den EGF-Rezeptor etabliert sind.

Abstract

Basics of Tumor Development and Importance of Human Papilloma Virus (HPV) for Head and Neck Cancer

Head and Neck Squamous Cell Carcinoma (HNSCC) are the 6th most common cancers worldwide. While the incidence of larynx-hypopharynx carcinoma decreases, actually an increase in oropharyngeal squamous cell carcinoma (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. Though, it was shown recently for 25 to 60% of OSCC, to be associated with an infection by oncogenic human papilloma virus (HPV). The development of “common” head-neck-tumors is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or to an activation of proto-oncogenes. A more or less uniform sequence of different DNA-damages leads to genetic instability. In this context, an early and frequent event is deletion on the short arm of chromosome 9, which results in inactivation of the p16-gene. On the contrary, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since E6 and E7 lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The process of natural transoral infection is not yet clear. However, as a matter of fact peroral HPV-infection is not seldom and in most cases such an infection heals completely and uneventfully. Smoking seems to increases the probability for developing an HPV-associated tumor. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of an HPV-association may become important for future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for instance regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, especially patients with HPV-associated OSCC may take advantage of a less aggressive postoperative treatment. Finally an outlook will be given on possible target-aimed therapies, of which so far only antibodies against EGF-receptors are established in clinical practice.

Schlüsselwörter

Kopf-Hals-Tumor - humane Papillomaviren - Karzinogenese - Prognose - molekulare Marker

Key words

head and neck cancer - human papillomavirus - carcinogenesis - prognosis - molecular markers

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