Head and Neck Paragangliomas (HNP) are hypervascular tumours characterised by a slow growth pattern and a strong hereditary context that originate from the neural crest derived paraganglia, which... Show moreHead and Neck Paragangliomas (HNP) are hypervascular tumours characterised by a slow growth pattern and a strong hereditary context that originate from the neural crest derived paraganglia, which are associated with the autonomous nervous system and are situated at several locations in the head and neck region. Inactivating mutations in subunits of complex II (SDH) of the mitochondrial respiratory chain are responsible for hereditary tumours and have lead to a novel concept of mitochondrial tumoursupressor-genes and further insight in the intricate association of cellular oxygen sensing mechanisms and (pseudo)-hypoxia as environmental risk factors. However, further characterisation of the tumour biology is warranted for better understanding of the natural behaviour of HNP and possible identification clinicopathological parameters that could aid the clinician in his treatment decisions. In this thesis several studies on the molcular pathology of HNP are discussed including genotype-fenotype relations, the role of bFGF in tumourgenisis, the interplay between proliferation, cell cycle activity and apoptosis, and the nature of sustentacular cells in these apparent biphasic tumours. Additionally, in a clincal study the prevalence of synchronic or metachronic pheochromocytomas in patients with SDHD-linked HNP was determined. Show less
Cholesteatoma is a benign, gradually expanding destructive epithelial lesion of the temporal bone, often accompanied with inflammation. The complications can be severe, e.g., destruction of the... Show moreCholesteatoma is a benign, gradually expanding destructive epithelial lesion of the temporal bone, often accompanied with inflammation. The complications can be severe, e.g., destruction of the ossicular chain and otic capsule with consecutive hearing loss. Several hypotheses for the pathogenesis of human cholesteatoma have been proposed but are still controversial. In this thesis, protein signaling pathways were investigated which are involved in different aspects of cholesteatoma pathogenesis, such as hyperproliferation, aberrant differentiation, and extra-cellular matrix deposition. In cholesteatoma epithelium increased expressions of those proteins were found which are involved in proliferation (Ki-67), cell cycle arrest (p53, p21), early terminal differentiation (involucrin) and survival (pAKT). The proteins of which the expressions were decreased were those concerning late terminal differentiation (filaggrin) and apoptosis (active caspase 3). Moreover, increased activation of MAPK- and its association with TGF_ cellular signaling cascades were demonstrated. In cholesteatoma stroma, increased extracellular matrix deposition, visualized by accumulation of EDA-Fibronectin, was present. These results were placed in the context of the interconnected signaling processes of wound healing. Concluding: cholesteatoma behaves as a chronic wound in which a persistent inflammation appears to be a contributing factor to its chronicity. Research into pharmacological interventions aimed at control of inflammation is recommended. Show less
