Aetiology

Acromegaly is due to a pituitary somatotroph adenoma in about 95% to 99% of cases. Rarely (1%), ectopic tumours secreting growth hormone-releasing hormone (GHRH) or growth hormone (GH), or both are the cause of acromegaly.[4]​ Prolactin is co-secreted, either by a mammosomatotroph tumour or a mixed lactotroph and somatotroph tumour, in 30% to 40% of cases.[5]​ In rare cases, somatotroph hyperplasia occurs in patients with neuroendocrine tumours (hypothalamic or digestive) that over-produce GH or GHRH.[7] Several studies examining X-chromosome inactivation have shown that human pituitary adenomas are monoclonal in origin. This suggests that pituitary tumours arise from the proliferation of single, mutated pituitary cells, where genetic alterations promote cellular growth rate. Indeed, the activating mutation in the GNAS1 gene (the G protein Gs-alpha; termed gsp oncogene) is shown in 30% to 40% of somatotroph adenomas, leading to constitutive activation of the GHRH receptor and subsequent activation of adenylyl cyclase, somatotroph proliferation, and GH hypersecretion. Genetic predisposition to pituitary tumours is considered rare overall, but several mutations have been discovered.[7]

Pathophysiology

Pituitary cells are physiologically regulated by hormones, transcription factors, and growth factors that stimulate their proliferation and hormone production throughout life. Dysregulation of these signalling pathways can promote tumour development. Pituitary somatotroph adenomas chronically secrete excessive GH, which stimulates insulin-like growth factor 1 production leading to the majority of the clinical manifestations of the disease.[7]

Classification

Pituitary adenoma classification

Most clinicians use a simple classification according to the tumour size (microadenomas [<10 mm diameter] versus macroadenomas) and extension or invasiveness (suprasellar versus parasellar).

World Health Organization (WHO) classification of tumours of the central nervous system[1]

Tumours of the sellar region:

  • Adamantinomatous craniopharyngioma

  • Papillary craniopharyngioma

  • Pituicytoma, granular cell tumour of the sellar region, and spindle cell oncocytoma

  • Pituitary adenoma/pituitary neuroendocrine tumour (PitNET)

  • Pituitary blastoma

Pathological classification of pituitary adenomas/PitNET

The 2021 WHO classification continues to follow the 2017 (4th edition) WHO classification categorises adenomas according to their pituitary cell lineage rather than according to a hormone-producing pituitary adenoma.[1]​[2]​​[3]​​

The cell lineages of differentiation and morphological variants that secrete GH are:

Somatotroph adenomas

  • Densely granulated adenoma

  • Sparsely granulated adenoma

  • Mammosomatotroph adenoma

  • Mixed somatotroph-lactotroph adenoma

Lactotroph adenomas

  • Acidophilic stem cell adenoma

Plurihormonal adenomas

  • Plurihormonal PIT-1 positive adenoma (previously called silent subtype 3 adenoma)

  • Adenomas with unusual immunohistochemical combinations.

Positive GH immunostaining in a patient with clinical features of acromegaly and elevated IGF-1 confirms the diagnosis of a pituitary GH-secreting adenoma.

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