Ieva Lase: Ectopic hormone secretion from neuroendocrine neoplasms: Clinical and molecular studies

Abstract

Ectopic hormone secretion from neuroendocrine neoplasms (NENs) is rare and associated with increased morbidity and mortality. ACTH-secreting NENs causing ectopic Cushing’s syndrome (ECS) are well studied, however, existing evidence is limited to small cohorts. The predictive value of hormone secretion in lung-NENs has not been widely studied. The aim of this thesis was to evaluate ACTH secreting NENs and ectopic hormone secretion in lung-NENs.

In the first paper we analysed a cohort of 51 patients with ECS. The secretion of multiple hormones in parallel, high morning cortisol, higher tumour grade, and the presence of diabetes mellitus were associated with shorter overall survival (OS). The development of ECS in non-functioning NENs was associated with tumour progression. Next, we evaluated bilateral adrenalectomy (BA) as a treatment option in ECS. Despite the frequent use of steroidogenesis inhibitor treatment, BA was necessary in a majority of patients. Significantly fewer severe complications were observed in the endoscopic group compared to open surgery (p=0.030). The two-surgeon approach BA should be considered as the method of choice in ECS when compared with other BA approaches, due to fewer complications and shorter operating time (p=0.001). The third paper demonstrated that severe hypokalaemia (< 2.5 mmol/l) at diagnosis was present in 50% of patients with ECS and was associated with shorter OS (12 months vs. 39 months, p=0.009). Hypercortisolaemia in combination with severe hypokalaemia at diagnosis of ECS is an acute life-threatening situation and immediate actions should be considered to reduce cortisol levels, primarily BA. Finally, a separate analysis of hormone secreting lung-NENs, including immunohistochemical staining for hormones was performed. Fifty-two patients out of 127 tested had elevated hormone levels with predominance of serotonin. In this lung-NEN cohort, diffuse calcitonin staining and multiple hormone secretion was associated with shorter OS (p=0.036 resp. 0.002).

In summary, this thesis contributes to a better understanding of a very rare condition and highlights the importance of intensified clinical management in ECS, particularly in cases with multiple hormone secretion. It also demonstrates hormone secretion and high calcitonin expression in tumour tissue in lung-NENs as negative prognostic factors