PAL1 Pituitary Tumours

• Pituitary tumours

  Benign tumours of the pituitary gland

  
• Pituitary gland

  • Small, bean-shaped structure that lies at the base of the brain within the confines of the sella turcica
  • Composed of two lobes, anterior lobe (adenohypophysis) and posterior lobe (neurohypophysis)
  • Connected to the hypothalamus by the stalk, which has portal vessels carrying blood from the hypothalamus to the anterior lobe and nerve fibres to the posterior lobe
  • Enclosed in the sella turcica
  • Bridged over by a fold of dura mater called the diaphragma sellae
  • Located with the sphenoidal air sinuses below
  • Located with the optic chiasm above
  • Located with the cavernous sinuses at the lateral – cavernous sinus contain 3rd, 4th and 6th cranial nerves and internal carotid arteries

  
• Normal anterior pituitary gland

  • Arranged in relatively evenly sized clusters of cells, known as acini, which contain an assortment of cell types and these cells are outlined by reticulin fibers
  • Contains prolactin (PRL) and growth hormone (GH) positive cells, ACTH positive cells, and lesser extent TSH-positive cells

  
• Normal posterior pituitary

  • More histologically monotonous and composed of unmyelinated axons and specialized glia
  • The infundibular stalk is part of the posterior lobe and contains closely justaposed, thin-walled blood vessels that transport hypothalamic release and release-inhibiting factors to the anterior gland

  
• Types of pituitary tumours

  • Pituitary adenomas
  • Craniopharyngioma
  • Granular cell tumour of neurohypophysis
  • Mixed pituitary adenoma-gangliocytoma
  • Pituitary carcinoma
  • Metastatic tumours

  
• Pituitary adenomas

  • Most common of the anterior pituitary tumours
  • Primary and metastatic carcinomas are rarely seen
  • Other benign pituitary tumours which can be found occasionally are craniopharyngioma and granular cell tumour (choristoma)

  
• Functional pituitary adenomas

  Associated with hormone excess and clinical manifestations

  
• Nonfunctioning pituitary adenomas

  There is no production of hormone

  
• Silent adenomas


  Hormone production can be demonstrated only at the tissue level<|>There is no clinical manifestations due to excess hormone secretion<|>Clinically noticeable when the tumour causes local mass effect (compress on adjacent structures)

  
• In most cases, both functional and nonfunctioning pituitary adenomas usually are composed of a single cell type and produce a single predominant hormone
• Some pituitary adenomas can secrete two different hormones (growth hormone and prolactin being the most common combination)

  
• Functioning adenomas

  Associated with distinct endocrine signs and symptoms
• Nonfunctioning and hormone-negative adenomas

  Likely to come to clinical attention at a later stage – therefore they are more likely to be macroadenomas<|>May cause hypopituitarism as they encroach on and destroy adjacent anterior pituitary parenchyma

  
• Plurihormonal pituitary adenomas

  Rare

  
• Pathogenesis of pituitary adenomas

  1. G protein mutations

  2. Familial pituitary adenomas

  3. Invasive pituitary adenomas

  
• G protein mutations

  G proteins have a critical role in transmitting signals from cell surface receptors to intracellular effectors, which then generate second messenger (cAMP)<|>Mutation in GNAS1 gene which encodes G protein α subunit interferes with its intrinsic GTPase activity – which results in constitutive activation of G protein and persistent generation of cAMP – which leads to unchecked cellular proliferation<|>Approximately 40% of growth hormone-secreting somatotroph cell adenomas have mutations of the GNAS1 gene

  
• Familial pituitary adenomas

  Approximately 5% of pituitary adenomas arise as a consequence of an inherited predisposition<|>Four genes have been identified as a cause: MEN1, CDKN1B, PRKAR1A, and AIP<|>MEN1 gene mutation causes multiple endocrine neoplasia syndrome 1 (MEN1)<|>AIP (Aryl hydrocarbon receptor-interacting protein) gene mutation causes growth hormone (GH) secreting adenomas at a younger age (before 35 years)
• Invasive pituitary adenomas

  Mutations of TP53 gene is associated with a propensity for an adenoma with an aggressive behaviour, such as invasion and recurrence<|>Activating mutations of the RAS oncogene are observed in rare pituitary carcinomas

  
• Gross morphology of pituitary adenomas

  • Usually presented as well-circumscribed soft lesion in the sellar region
  • Large pituitary tumour can extend beyond the sella turcica and compress on the adjacent structures
  • Distortion of an overlying brain parenchyma and lateral ventricles can be seen
  • Foci of haemorrhage and/or necrosis are common in macroadenomas
  • Microadenoma: < 10 mm in size
  • Macroadenoma: > 1 cm in size
  • Small lesions are confined to the the sella turcica

  
• Microscopic findings of pituitary adenomas

  • Composed of relatively uniform, polygonal cells arrayed in sheets, cords, or papillae
  • Composed predominantly of one of the normal cell types of the anterior pituitary (cytoplasm may be acidophilic or basophilic or chromophobic)
  • Supporting connective tissue or reticulin is sparse
  • Cellular monomorphism and absence of reticulin network

  
• Functional classification of pituitary adenomas

  • Lactotroph (prolactin PRL-secreting) adenoma
  • Somatotroph (growth hormone GH-secreting) adenoma
  • Corticotroph (Adrenocorticotropic hormone ACTH-secreting) adenoma
  • Mixed somatotroph-lactotroph (GH-PRL-secreting) adenoma
  • Gonadotroph (FSH-LH-secreting adenoma)
  • Null-cell (endocrinologically inactive) adenoma
  • Oncocytoma
  • Pleurihormonal adenoma

  
• Pituitary apoplexy

  Condition in which the pituitary tumor spontaneously hemorrhages (bleeds)<|>Can also describe a less common condition when a pituitary tumor outgrows its blood supply (a stroke)<|>Clinical features: Headache, visual field defect (most common – bitemporal hemianopia), altered consciousness, hypopituitarism

  
• Pressure effects of pituitary adenomas

  Expansion of the lesion resulting in destruction of the surrounding glandular tissue by pressure atrophy<|>Erosion and enlargement of sella turcica<|>Extension of the tumour damaging the optic chiasm, optic nerves, neurohypophysis and adjacent cranial nerves<|>Rarely, downward extension into the nasopharynx

  
• Hormonal effects of pituitary adenomas

  Depending upon their cell types, pituitary adenomas produce excess of pituitary hormones and the corresponding clinical syndromes of hyperpituitarism

  
• Functioning pituitary adenomas

  Lactotroph adenoma, Somatotroph adenoma, Corticotroph adenoma, Thyrotroph adenoma, Gonadotroph adenoma, Mixed Somatotroph-lactotroph adenoma, Pleurihormonal adenoma
• Hyperfunction of the anterior pituitary is due to the development of a hormone-secreting pituitary adenoma (Functioning Adenomas), and rarely, a carcinoma

  
• Sellar mass

  Compression of 3rd, 4th or 6th nerve – diplopia and strabismus
• sella turica
• Bitemporal hemianopid
• Functioning adenomas and Hyperpituitarism

  Hyperpituitarism is characterised by hypersecretion of one or more of the pituitary hormones

  
• Hypersecretion of pituitary hormones

  May be due to diseases of the anterior pituitary, posterior pituitary or hypothalamus

  
• Hyperfunction of the anterior pituitary

  Due to the development of a hormone-secreting pituitary adenoma (Functioning Adenomas), and rarely, a carcinoma

  
• Functioning pituitary adenomas

  • Lactotroph adenoma
  • Somatotroph adenoma
  • Corticotroph adenoma
  • Thyrotroph adenoma
  • Gonadotroph adenoma
  • Mixed Somatotroph-lactotroph adenoma
  • Pleurihormonal adenoma
• Hyperfunction of anterior pituitary

  Can cause gigantism and acromegaly, hyperprolactinaemia and Cushing's syndrome
• Somatotroph Adenomas

  Growth hormone-secreting somatotroph adenomas are usually clinically active<|>They cause gigantism in children and acromegaly in adult<|>Most cases of somatotroph adenomas are macroadenomas

  
• Somatotroph Adenomas

  • Microscopic finding: CAM5.2 immunostaining (IHC) shows presence of ball-like (dot-like) cytoplasmic fibrous bodies in >70% of cells
  • Anti-GH antibody staining demonstrates growth hormone within the cytoplasm of the cells

  
• Gigantism

  Growth hormone (GH) excess occurs prior to the closure of the epiphyseal plate – excessive level of GH together with the insulin-like growth factor 1 (IGF1) result in gigantism
• Acromegaly

  Growth hormone (GH) excess occurs after closure of the epiphyseal plate – excessive level of GH together with the insulin-like growth factor 1 (IGF1) result in acromegaly<|>The most common (>95%) cause of acromegaly is pituitary adenoma (somatotroph adenoma)
• Clinical Features of acromegaly

  • Enlargement of hands and feet
  • Changes in facial features
  • Prominent lower jaw and Prognathism
  • Broadening of lower face
  • Prominent supraorbital ridges
  • Frontal bossing
  • Enlargement of tongue (macroglossia) and lips
  • Headache and visual field defects
  • Thickening of the skin
• Complications of acromegaly

  • Dilated cardiomyopathy
  • Increased risk of colorectal cancer
  • Visceral organomegaly with dysfunction (Liver, Kidneys, thyroid)
  • Hyperglycaemia and Diabetes mellitus
  • Hypertension