Hereditary phaeochromocytoma and paraganglioma in SDHB pathogenic variant carriers: clinical outcomes, surveillance strategies and economic evaluation

Abstract

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours. Around 10-15% are caused by germline variants in the succinate dehydrogenase (SDH) gene family. Carriers of SDHB pathogenic variants (PVs) face high risk of recurrence, metastasis and death. Surveillance is recommended, but many uncertainties remain. These include true penetrance, predictors of progression, psychosocial burden and cost-effectiveness.

This thesis aimed to provide evidence to guide surveillance, genetic counselling and management of SDHB PV carriers. Chapter 2 presented a multicentre cohort study. Surveillance enabled earlier tumour detection. Carriers detected through surveillance had smaller tumours, higher surgical cure rates and better survival than those detected due to symptoms. Chapter 3 investigated inheritance patterns. Transmission ratio distortion was demonstrated, with PVs inherited more often than predicted by Mendelian genetics. This finding had implications for genetic counselling.

Chapter 4 assessed quality of life in carriers. Carriers had lower health utility scores than population norms. Anxiety and depression were common, even in carriers without tumours. This highlighted the psychosocial cost of lifelong surveillance. Chapter 5 was a systematic review and meta-analysis. It showed that penetrance rose steadily with age. Carriers remain at risk of second tumours after treatment. Lifetime risk of metastasis in non-probands was lower than earlier reports, but still significant. Chapter 6 developed a Markov model of different frequencies of surveillance. Annual surveillance achieved slightly higher QALYs but at greater cost compared to 3- and 5-yearly strategies. Results were highly sensitive to assumptions about anxiety from more frequent surveillance.

In conclusion, this thesis integrated clinical, genetic, psychosocial and economic perspectives. It provides an evidence base for surveillance and genetic counselling in SDHB PV carriers.