SDHD-related head and neck paragangliomas are, hereditary and generally benign, neuroendocrine tumors that arise from paraganglionic tissue associated with the parasympathetic nervous system.... Show moreSDHD-related head and neck paragangliomas are, hereditary and generally benign, neuroendocrine tumors that arise from paraganglionic tissue associated with the parasympathetic nervous system. The primary aim of this thesis was to gain more insight in the natural course of SDHD-related head and neck paragangliomas and ultimately improve surveillance and treatment strategies, as well as counseling of both patients and their family members. The risk of occult and metachronous paragangliomas, tumor growth, clinical progression and survival of SDHD germline mutation carriers were addressed. Show less
This thesis aims to assess clinical characteristics of paraganglioma (PGLs) patients, with focus on SDH mutation carriers, evaluate psychological aspects in these subjects and to review various... Show moreThis thesis aims to assess clinical characteristics of paraganglioma (PGLs) patients, with focus on SDH mutation carriers, evaluate psychological aspects in these subjects and to review various treatment options for PGLs. Show less
The findings of the present thesis can be summarized in the following conclusions: 1. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of... Show moreThe findings of the present thesis can be summarized in the following conclusions: 1. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of one single SDHD mutation, the SDHD-c.274G>T (p.Asp92Tyr) mutation. 2. Patients with head-and-neck paragangliomas have a considerable impairment of quality of life. 3. Patients with head-and-neck paragangliomas have serious subjective sleep complaints. 4. Patients with SDHD-associated head-and-neck paragangliomas have an increased risk for development of pheochromocytomas and paragangliomas at other locations and life long, repetitive follow up with protocolized clinical, biochemical and radiological screening is therefore mandatory. 5. The use of [123I]-MIBG for detection of intra- and extra-adrenal paragangliomas combined, revealed a sensitivity and specificity of only 80% and 75%, respectively. The sensitivity is dependent on tumor localization and tumor behavior, with an increase in sensitivity to 92% if (intra-adrenal) pheochromocytomas are investigated separately. 6. The practical clinical implications of non-secreting intra-adrenal paragangliomas are currently uncertain. 7. Patients with SDHD mutations have malignant disease in at least ~2.5% of the cases. 8. Mediastinal paragangliomas are associated with mutations in the succinate dehydrogenase genes (either SDHB or SDHD) and aggressive behavior and might be more prevalent than hitherto appreciated. 9. Although the consequences of missing non-secreting and mediastinal paragangliomas in an SDHD-associated population are currently unclear, their possible presence should be taken into consideration in the development of future screening protocols. 10. In the future, [18F]-FDOPA and/or [18F]-FDA are expected to (at least partly) replace MIBG in diagnostic imaging for pheochromocytoma and paraganglioma. Show less
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
