Pituitary Tumors – Symptoms And Causes

Pituitary Gland

Pituitary Gland Normal Structure:

Anatomy The pituitary gland or hypophysis in an adult weighs about 500 mg and is slightly heavier in females. It is situated at the base of the brain in a hollow called sella turcica formed out of the sphenoid bone. The gland is composed of 2 major anatomic divisions the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis).

• The anterior lobe or adenohypophysis is an ectodermal derivative formed from Rathke’s pouch which is an upward diverticulum from the primitive buccal cavity. The adenohypophysis has no direct neural connection but has an indirect connection through capillary portal circulation by which the anterior pituitary receives the blood which has already passed through the hypothalamus.
• The posterior lobe or neurohypophysis is a down growth from primitive neural tissue. The neurohypophysis, therefore, has a direct neural connection superiorly with the hypothalamus.

Pituitary Gland Histology And Functions Histology and functions of the anterior and posterior lobes of the pituitary gland are quite distinct.

Read And Learn More: Systemic Pathology Notes

Anterior Lobe (Adenohypophysis): It is composed of round to polygonal epithelial cells arranged in cords and islands having fibrovascular stroma. These epithelial cells, depending upon their staining characteristics and functions, are divided into 3 types, each of which performs separate functions:

1. Chromophil cells with acidophilic granules: These cells comprise about 40% of the anterior lobe and are chiefly located in the lateral wings. The acidophils are further of 2 types:

1. Somatotrophs (GH cells) produce growth hormone (GH).
2. Lactotrophs (PRL cells) produce prolactin (PRL).

Cells containing both GH and PRL called mammosomatotrophs are also present.

2. Chromophil cells with basophilic granules: These cells constitute about 10% of the anterior lobe and are mainly found in the region of the median wedge. The chromophile includes 3 types of cells:

1. Gonadotrophs (FSH-LH cells) which are the source of the FSH and LH or interstitial cell-stimulating hormone (ICSH).
2. Thyrotrophs (TSH cells) are the cells producing TSH.
3. Corticotrophs (ACTH-MSH cells) produce ACTH, melanocyte-stimulating hormone (MSH), β-lipoprotein and β-endorphin.

3. Chromophobe cells without visible granules: These cells comprise the remaining 50% of the adenohypophysis. These cells by light microscopy contain no visible granules, but electron microscopy reveals sparsely granulated corticotrophs, thyrotrophin and gonadotrophs.

All these functions of the adenohypophysis are under the indirect control of the hypothalamus through stimulatory and inhibitory factors synthesised by the hypothalamus which reach the anterior lobe through capillary portal blood.

Posterior Lobe (Neurohypophysis): Neurohypophysis is composed mainly of interlacing nerve fibres in which are scattered specialised glial cells called pituicytes. These nerve fibres on electron microscopy contain granules of neurosecretory material made up of 2 octapeptides vasopressin or antidiuretic hormone (ADH), and oxytocin, both of which are produced by neurosecretory cells of the hypothalamus but are stored in the cells of the posterior pituitary.

1. ADH: It causes the reabsorption of water from the renal tubules and is essential for the maintenance of osmolality of the plasma. Its deficiency results in diabetes insipidus characterised by uncontrolled diuresis and polydipsia.

2. Oxytocin: It causes contraction of mammary myoepithelial cells resulting in the ejection of milk from the lactating breast and causes contraction of the myometrium of the uterus at term. It is obvious from the description above that pituitary, though a tiny organ, is concerned with a variety of diverse functions in the body.

• The pituitary gland and hypothalamus are so closely interlinked that diseases of the pituitary gland involve the hypothalamus, and dysfunctions of the hypothalamus result in secondary changes in the pituitary.
• The pituitary gland is involved in several diseases which include: non-neoplastic (for example inflammations, haemorrhage, trauma, infarction and many other endocrine diseases) and neoplastic diseases.
• However, functionally and morphologically, diseases of the pituitary (anterior and posterior pituitary, and hypothalamus), include: hyperpituitarism, hypopituitarism, and pituitary tumours.

Hyperpituitarism

• Hyperpituitarism is characterised by the oversecretion of one or more of the pituitary hormones. Such hypersecretion may be due to diseases of the anterior pituitary, posterior pituitary or hypothalamus.
• For all practical purposes, however, hyperfunction of the anterior pituitary is due to the development of a hormone-secreting pituitary adenoma (discussed later), and rarely, a carcinoma.
• For each of the hormonal hyperfunctions of the anterior pituitary, posterior pituitary and hypothalamus, a clinical syndrome is described. A few important syndromes are as follows:

Hyperfunction Of Anterior Pituitary

Three common syndromes of adenohypophyseal hyperfunction are gigantism and acromegaly, hyperprolactinaemia and Cushing’s syndrome.

Gigantism And Acromegaly: Both these clinical syndromes result from sustained excess of growth hormone (GH), most commonly by somatotroph (GH-secreting) adenoma. Gigantism When GH excess occurs prior to epiphyseal closure, gigantism is produced.

• Gigantism, therefore, occurs in prepubertal boys and girls and is much less frequent than acromegaly. The main clinical feature of gigantism is the excessive and proportionate growth of the child.
• There is enlargement as well as thickening of the bones resulting in a considerable increase in height and enlarged thoracic cage.

Acromegaly: Acromegaly results when there is overproduction of GH in adults following cessation of bone growth and is more common than gigantism. The term ‘acromegaly’ means increased growth of extremities (acro = extremity).

• There is the enlargement of hands and feet, coarseness of facial features with the increase in soft tissues, prominent supraorbital ridges and a more prominent lower jaw which when clenched results in protrusion of the lower teeth in front of upper teeth (prognathism).
• Other features include enlargement of the tongue and lips, thickening of the skin and kyphosis. Sometimes, a few associated features such as TSH excess resulting in thyrotoxicosis, and gonadotropin insufficiency causing amenorrhoea in the females and impotence in the male, are found.

Prolactinaemia: Prolactinaemia is due to lactotroph (PRL-secreting) pituitary adenoma, also called prolactinoma having excessive production of prolactin. Occasionally, hyperprolactinaemia results from hypothalamic inhibition of PRL secretion by certain drugs (for example chlorpromazine, reserpine and methyl-dopa).

• In females, hyperprolactinaemia causes amenorrhoea-galactorrhoea syndrome characterised clinically by infertility and expression of a drop or two of milk from the breast, not related to pregnancy or puerperium. In males, it may cause impotence or reduced libido.
• These features result either from associated inhibition of gonadotropin secretion or interference in gonadotropin effects.

Cushing’S Syndrome: Pituitary-dependent Cushing’s syndrome results from ACTH excess. Most frequently, it is caused by corticotroph (ACTH-secreting) adenoma. Cushing’s syndrome is discussed under diseases of the adrenal gland.

Hyperfunction Of Posterior Pituitary And Hypothalamus:

Lesions of the posterior pituitary and hypothalamus are uncommon. Two of the syndromes associated with hyperfunction of the posterior pituitary and hypothalamus are the inappropriate release of ADH and precocious puberty.

Inappropriate Release Of Adh: Inappropriate release of ADH results in its excessive secretion which manifests clinically by the passage of concentrated urine due to increased reabsorption of water and loss of sodium in the urine, consequent hyponatraemia, haemodilution and expansion of intra- and extracellular fluid volume.

• Inappropriate release of ADH occurs most often in paraneoplastic syndrome e.g. in neuroendocrine tumours of the lung, carcinoma of the pancreas, lymphoma and thymoma.
• Infrequently, lesions of the hypothalamus such as trauma, haemorrhage and meningitis may produce ADH hypersecretion. Rarely, pulmonary diseases such as tuberculosis, lung abscess, pneumoconiosis, empyema and pneumonia may cause overproduction of ADH.

Precocious Puberty: A tumour in the region of the hypothalamus or the pineal gland may result in premature release of gonadotropins causing the onset of pubertal changes prior to the age of 9 years.

The features include premature development of genitalia both in the male and in the female, growth of pubic hair and axillary hair. In the female, there is breast growth and onset of menstruation.

Hypopituitarism:

In hypopituitarism, there is usually a deficiency of one or more of the pituitary hormones affecting either the anterior pituitary or posterior pituitary and the hypothalamus.

Hypofunction Of Anterior Pituitary

• Adenohypophyseal hypofunction is invariably due to the destruction of the anterior lobe of more than 75% because the anterior pituitary possesses a large functional reserve. This may result from anterior pituitary lesions or pressure and destruction from adjacent lesions.
• Lesions of the anterior pituitary include nonsecretory (chromophobe) adenoma, metastatic carcinoma, craniopharyngioma, trauma, postpartum ischaemic necrosis (Sheehan’s syndrome), empty-sella syndrome, and rarely, tuberculosis.
• Though a number of syndromes associated with deficiency of anterior pituitary hormones have been described, two important syndromes are panhypopituitarism and dwarfism.

Panhypopituitarism: The classical clinical condition of major anterior pituitary insufficiency is called panhypopituitarism. Three most common causes of panhypopituitarism are non-secretory (chromophobe) adenoma (discussed later), Sheehan’s syndrome and Simmond’s disease, and empty-sella syndrome.

Sheehan’s syndrome and Simmond’s disease: Pituitary insufficiency occurring due to postpartum pituitary (Sheehan’s) necrosis is called Sheehan’s syndrome, whereas the occurrence of the similar process without preceding pregnancy, as well as its occurrence in males, is termed Simmond’s disease.

• The main pathogenetic mechanism underlying Sheehan’s necrosis is the enlargement of the pituitary occurring during pregnancy which may be followed by hypotensive shock precipitating ischaemic necrosis of the pituitary.
• Other mechanisms hypothesised are DIC following delivery, traumatic injury to vessels, and excessive haemorrhage. Patients with longstanding diabetes mellitus appear to be at greater risk of developing this complication.
• The first clinical manifestation of Sheehan’s syndrome is the failure of lactation following delivery which is due to a deficiency of prolactin.
• Subsequently, other symptoms develop which include loss of axillary and pubic hair, amenorrhoea, sterility and loss of libido. Concomitant deficiency of TSH and ACTH may result in hypothyroidism and adrenocortical insufficiency.

Morphologic Features: Sheehan’s syndrome during the early stage shows ischaemic necrosis and haemorrhage in the anterior pituitary, while later necrotic tissue is replaced by fibrous tissue.

Empty-sella syndrome: Empty-sella syndrome is characterised by the appearance of an empty sella and features of panhypopituitarism. Most commonly, it results from herniation of subarachnoid space into the sella turcica due to an incomplete diaphragm sella creating an empty sella.

• Other less common causes are Sheehan’s syndrome, infarction and scarring in an adenoma, irradiation damage, or surgical removal of the gland.
• Pituitary Dwarfism Severe deficiency of GH in children before epiphyseal closure results in retarded growth and pituitary dwarfism. Most commonly, isolated GH deficiency is the result of an inherited autosomal recessive disorder.
• Less often, it may be due to a pituitary adenoma or craniopharyngioma, infarction and trauma to the pituitary. The clinical features of inherited cases of pituitary dwarfism appear after one year of age.
• These include proportionate retardation in the growth of bones, normal mental state for age, poorly-developed genitalia, delayed puberty and episodes of hypoglycaemia.
• The pituitary dwarf must be distinguished from the hypothyroid dwarf (cretinism) in which there is achondroplasia and mental retardation.

Hypofunction Of Posterior Pituitary And Hypothalamus

Insufficiency of the posterior pituitary and hypothalamus is uncommon. The only significant clinical syndrome due to hypofunction of the neurohypophysis and hypothalamus is diabetes insipidus.

Diabetes Insipidus: Deficient secretion of ADH causes diabetes Insipidus. The causes of ADH deficiency are inflammatory and neoplastic lesions of the hypothalami-hypophyseal axis, destruction of neurohypophysis due to surgery, radiation, head injury, and lastly, those cases where no definite cause is known and are labelled as idiopathic.

The main features of diabetes insipidus are excretion of a very large volume of dilute urine of low specific gravity, polyuria and polydipsia.

Pituitary Tumours

Tumours of the anterior pituitary are more common than those of the posterior pituitary and hypothalamus. The most common of the anterior pituitary tumours are adenomas; primary and metastatic carcinomas being rare. Craniopharyngioma is another benign pituitary tumour found occasionally.

All pituitary tumours, whether benign or malignant, cause symptoms in the following 2 ways:

1. Pressure effects: These are caused by the expansion of the lesion resulting in the destruction of the surrounding glandular tissue by pressure atrophy.
   • This causes erosion and enlargement of sella turcica, upward extension of the tumour damaging the optic chiasma, optic nerves, neurohypophysis and adjacent cranial nerves, and rarely, downward extension into the nasopharynx.
2. Hormonal effects: Depending upon their cell types, pituitary adenomas produce an excess of pituitary hormones and the corresponding clinical syndromes of hyperpituitarism. Infarction and destruction of adenoma may cause symptoms of hypopituitarism.

Pituitary Adenomas

Adenomas are the most common pituitary tumours. They are conventionally classified according to their H & E staining characteristics of granules into acidophil, basophil and chromophobe adenomas.

However, this morphologic classification is considered quite inadequate because of the significant functional characteristics of each type of adenoma including the chromophobe adenoma, which on H & E staining does not show visible granules.

As per the WHO classification (2017), pituitary adenomas are classified according to pituitary adenohypophysealcell lineage requiring assessment of pituitary transcription factor; the following three groups are identified:

1. Acidophilic lineage: main transcription factor/s PIT-1 for somatotrophs, PIT-1 and ER- α for lactotrophs, PIT-1 and GATA-2 for thyrotrophin
2. Corticotroph lineage: main transcription factor T-PIT
3. Gonadotroph lineage: main transcription factor SF-1, GATA-2, ER-α for gonadotrophs Based on these criteria, morphologic variants are described according to pituitary hormone content, and specific histological and immunohistochemical features.

Morphologic Features Grossly, pituitary adenomas range in size from small foci of less than 10 mm in size (termed microadenoma) to large adenomas several centimetres in diameter (>1 cm called macroadenomas). They are spherical, soft and encapsulated.

Histologically, by light microscopy of H & E stained sections, an adenoma is composed predominantly of one of the normal cell types of the anterior pituitary i.e. acidophil, basophil or chromophobe cells. These cells may have the following 3 types of patterns:

1. The diffuse pattern is composed of polygonal cells arranged in sheets with scanty stroma.
2. The sinusoidal pattern consists of columnar or fusiform cells with fibrovascular stroma around
   which the tumour cells are arranged.
3. The papillary pattern is composed of columnar or fusiform cells arranged around the fibrovascular core.

Functionally, the most common pituitary adenomas, in decreasing order of frequency, are lactotroph (PRL-secreting) adenoma, somatotroph (GH-secreting) adenoma and corticotroph (ACTH-secreting) adenoma. Infrequently, mixed somatotroph-lactotroph (GH-PRL-secreting) adenoma, gonadotroph (FSH-LH-secreting) adenomas and null-cell (endocrinologically inactive) adenomas or oncocytoma are found.

Pleurihormonal-pituitary adenoma, on the other hand, may have multiple hormone elaborations. Functional classification of pituitary adenoma can be done by carrying out specific immunostains against the hormone products.

Pituitary adenomas occur in the age group of the 3rd to 6th decade of life. They are mostly sporadic. Less than 5% are familial having germline mutation in the MEN1 gene. The latter cases occur as a part of multiple endocrine neoplasia type 1 (MEN-1) in which pituitary adenoma is associated with adenomas of pancreatic islets and parathyroids.

Sporadic cases appear to be due to genetic abnormalities of signalling pathways, particularly G protein mutations. Clinically, patients with pituitary adenomas generally have a combination of features of Zollinger-Ellison’s syndrome, hyperparathyroidism and hyperpituitarism.

Craniopharyngioma

Craniopharyngioma is a benign suprasellar tumour arising from remnants of Rathke’s pouch. It has 2 peaks of occurrence: children and young adults in the 1st to 2nd decade and then in adults past 6th decade. The tumour, though benign, compresses as well as invades the adjacent structures extensively.

Morphologic Features Grossly, the tumour is encapsulated, adherent to surrounding structures and is typically a cystic, reddish-grey mass. The fluid in the cystic cavity typically has the colour and consistency of machinery oil.

Histologically, craniopharyngioma closely resembles ameloblastoma of the jaw. It has the following histologic features:

1. Stratified squamous epithelium frequently lines a cyst and contains loose stellate cells in the centre.
2. Compact sheets, trabeculae and nodules of squamous cells (ameloblastic areas).
3. Nodules of anucleate ghost cell squames and wet keratin.
4. Degenerative changes with cystic change, sometimes calcification.

Diseases of Pituitary Gland

• Hyperpituitarism is the oversecretion of one or more of the pituitary hormones due to diseases of the anterior pituitary (for example gigantism, acromegaly, prolactinoma, Cushing’s syndrome), posterior pituitary or hypothalamus (for example inappropriate release of ADH, precocious puberty).
• In hypopituitarism, there is usually a deficiency of one or more of the pituitary hormones affecting either the anterior pituitary (for example Sheehan’s syndrome, empty sella syndrome, dwarfism), or posterior pituitary and hypothalamus (for example diabetes insipidus).
• Major pituitary tumours are adenomas (micro- and macroadenomas) and craniopharyngioma.