Molecular pathogenesis of pituitary tumours

Pituitary adenomas are discovered in up to 25% of unselected autopsies, however, clinically apparent tumours are considerably less common. The pituitary gland is composed of differentiated cell types: somatotrophs, lactotrophs, corticotrophs, thyrotrophs, and gonadotrophs. Tumours may arise from any of these cell types and their secretory products depend on the cell of origin. The functional classification of pituitary tumorus is based on identification of cell gene products by immunostaining or mRNA detection, as well as measurement of circulating tumour and target organ hormone levels. Oversecretion of adrenocorticotropic hormone (ACTH) results in cortisol excess with Cushing’s disease. Growth hormone overproduction leads to acromegaly with typical acral overgrowth and metabolic abnormalities. Prolactin hypersecretion results in hypogonadism and galactorrhoea. Rarely, thyroid-stimulating hormone (TSH) hypersecretion leads to goitre and thyrotoxicosis, and gonadotropin excess results in gonadal dysfunction (1). Mixed tumours cosecreting growth hormone with prolactin, TSH, or ACTH may also arise from single cells. Clinically nonfunctional tumours are those that do not efficiently secrete their gene products, and most commonly they are derived from gonadotroph cells. Pituitary tumours are further defined radiographically as microadenomas (<1 cm in diameter) or macroadenomas (>1 cm in diameter). However, this classification does not reflect whether the pituitary tumour is amenable to total resection and limits assessment of invasive progression during serial imaging. Therefore, it is useful to apply the classification proposed by Hardy in 1973 and modified by Wilson in 1990 (Table 2.3.2.1), whereby pituitary tumours are classified into one of five grades and one of six stages, providing important preoperative information.

Pituitary tumours cause morbidity by both abnormal hormone secretion as well as compression of regional structures. As a considerable proportion of patients do not achieve optimal therapeutic control of mass effects and/or hormone hypersecretion despite advances in therapeutic approaches, understanding pathogenesis and pituitary tumour growth patterns in individual patients will enable identification of subcellular treatment targets, ultimately decreasing tumour-related morbidity and mortality.

Determinants of initiation and progression of pituitary adenomas are not fully understood. This chapter describes a spectrum of mechanisms implicated in pituitary tumorigenesis, including the role of pituitary plasticity, imbalances in cell cycle regulation, transcription factors, signalling pathways, and angiogenesis (Fig. 2.3.2.1). Molecular events related to tumorigenesis in human pituitary adenoma subtypes are summarized in Table 2.3.2.2. The causal role for selected genetic imbalances leading to development of pituitary tumours has been confirmed in several transgenic mouse models (Table 2.3.2.3).