Endocrine system

Pituitary gland disorders

Structural defects of the pituitary gland are few, although functional abnormalities are potentially numerous, leading to under- or overproduction of one or more of the many hormones produced by the pituitary gland and its target endocrine glands.

The most important histopathological lesions of the pituitary gland are benign adenomas derived from the anterior pituitary (adenohypophysis). These commonly secrete anterior pituitary hormones and result in the development of endocrine syndromes. Adenomas may be derived from any of the normal anterior pituitary cell types and can be classified by the hormones they secrete:

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  Prolactinomas: secrete prolactin and may lead to infertility and, occasionally, inappropriate breast milk production.

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  Corticotroph adenomas: secrete adrenocorticotrophic hormone (ACTH) and result in Cushing’s disease ( Fig. 20.1 ).

  

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  Somatotroph adenomas: secrete excess growth hormone and lead to acromegaly or rarely gigantism ( Fig. 20.2 ) ( E-Fig. 20.1 G ).

  

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  Thyrotroph and gonadotroph adenomas: both types are rare.

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  Non-secretory adenomas: a large number of pituitary adenomas have no demonstrable hormone secretion; such tumours only become manifest by impinging on vital local structures such as the optic chiasm, causing visual disturbance, or by expanding to a size large enough to destroy the surrounding normal functioning tissue, resulting in clinical hypopituitarism .

Disorders of the thyroid gland

A variety of pathological processes may affect the thyroid gland ( E-Fig. 20.8 ), leading to either diminished or excessive output of the thyroid hormone thyroxine. Hypothyroidism may result from dysfunction at any level of the hypothalamo-pituitary-thyroid axis and, as such, may be regarded as either primary (arising from a disorder within the thyroid gland) or secondary (as a consequence of pituitary disease).

There are a number of causes of primary hypothyroidism, some of which have an autoimmune basis, for example Hashimoto’s thyroiditis ( Fig. 20.3 ) ( E-Fig. 20.2 ). Hypothyroidism can be treated with thyroid hormone supplementation in the form of thyroxine tablets.

As with hypothyroidism, hyperthyroidism (thyrotoxicosis) may be considered as primary (abnormality within the gland) or secondary (abnormality outside of gland). Most cases of hyperthyroidism arise as a result of diffuse hyperplasia of the thyroid acinar cells, most commonly in the condition known as Graves’ disease ( Fig. 20.4 ). Sometimes the hyperplasia is confined to a single benign thyroid adenoma ( E-Fig. 20.3 ) , a so-called toxic nodule . Nevertheless, most thyroid adenomas ( Fig. 20.6 ) are non-functional and do not lead to disturbances of thyroid hormone output.

Multinodular goitre is one of the most common types of thyroid tissue in which the thyroid becomes enlarged due to the presence of numerous hyperplastic thyroid nodules ( Fig. 20.5 ) ( E-Fig. 20.4 ).

Four main forms of thyroid carcinoma occur, namely papillary , follicular , medullary and anaplastic (in order of frequency). Papillary, follicular and anaplastic carcinomas arise from cuboidal follicular lining cells. Medullary carcinoma of the thyroid is an uncommon malignant tumour of calcitonin-producing (parafollicular or C) cells and is particularly notable for its production of amyloid. Examples of papillary, follicular and medullary carcinomas are illustrated in Fig. 20.7 . Anaplastic carcinomas usually occur in the very elderly and are composed of sheets of poorly differentiated cells with little cytoplasm. These tumours grow very rapidly and extensively invade local tissues, often presenting as a bulky mass in the neck associated with symptoms of tracheal compression. Lymphoma may also arise in the thyroid gland, usually following longstanding Hashimoto’s thyroiditis.

Disorders of the parathyroid glands

The overproduction of parathyroid hormone due to an underlying abnormality of the parathyroid gland may result in hyperparathyroidism leading to altered calcium metabolism, bone disease and hypercalcaemia. This may be primary, secondary or tertiary, depending on the underlying cause. Primary abnormalities of parathyroid hormone and carcinoma of the parathyroid are very rare (see Fig. 20.8 ).

Disorders of the adrenal glands

The adrenal gland ( Fig. 20.9A ) has two distinct morphological and functional components:

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  The cortex : This secretes three groups of steroid hormones, namely glucocorticoids (e.g. cortisol), mineralocorticoids (e.g. aldosterone) and small quantities of sex hormones. With the naked eye, the adrenal cortex appears yellow because of its high content of lipid (mainly cholesterol), which is the substrate for synthesis of steroid hormones.

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  The medulla : This forms part of the neuroendocrine system and is responsible for the production of the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine).

Disorders of the adrenal cortex

In response to acute stress, atrophy of the adrenal cortex ( Fig. 20.9B ) may arise as the normally lipid-rich cortical cells breakdown lipid for the production of steroid hormones, thus becoming lipid depleted . This is commonly seen in adrenal glands at post-mortem, particularly when a patient has died with features of shock. It is manifest by atrophy of the gland with loss of the normal lipid vacuolation of cells of the cortex seen on microscopy. Adrenocortical atrophy may also result from steroid therapy (iatrogenic) or, occasionally, through primary autoimmune disease (Addison’s disease) . Other important, though less common, causes of adrenocortical insufficiency are tumour metastases and Waterhouse–Friderichsen syndrome in which there is haemorrhage of both adrenal glands caused by coagulation abnormality in the setting of bacterial meningitis.

In contrast to the picture with acute stress, with more prolonged stress the adrenal glands may become enlarged through hypertrophy and hyperplasia of cortical cells. Alternatively, hyperplasia of the adrenal cortex ( Figs 20.9C and 20.9D ) may arise as a consequence of prolonged stimulation of the adrenal cortex by pituitary-derived adrenocorticotrophic hormone (ACTH; Cushing’s disease ) or secretion of ectopic ACTH by non-pituitary tumours (Cushing’s syndrome) .

The adrenal cortex may be the site of benign adrenocortical adenomas ( Fig. 20.10 ) or, rarely, malignant adrenocortical carcinomas . These tumours of the adrenal cortex may be functional, resulting in the following endocrine syndromes:

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  Cushing’s syndrome: caused by cortisol secreting tumours

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  Conn’s syndrome: resulting from aldosterone secreting tumours

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  Adrenogenital syndrome: owing to excess production of androgens.

Often, cortical hyperplasia is nodular rather than diffuse and it may be difficult to distinguish between a benign cortical adenoma and a large nodule forming part of nodular cortical hyperplasia.

Disorders of the adrenal medulla

Developmentally, the adrenal medulla arises from embryonal neural crest cells and is part of the para-ganglion system along with a number of clusters of cells known as the extra-adrenal paraganglia , of which the carotid body is perhaps the best known. This paraganglion system is closely associated with the functioning of the autonomic nervous system.

The most important lesions of the adrenal medulla are tumours of the catecholamine-producing (chromaffin) cells, known as phaeochromocytoma , or neuronal tumours ( neuroblastomas , ganglion cell tumours ).

Phaeochromocytomas ( Fig. 20.11 ) ( E-Fig. 20.5 ) produce excessive adrenaline and noradrenaline and are usually benign. When these originate outwith the adrenal gland, they are referred to as extra-adrenal paragangliomas ( Fig. 20.12 ). In some cases, these are associated with familial syndromes such as von Hippel–Lindau syndrome (VHL). Some familial syndromes such as succinic dehydrogenase B (SDH-B) deficiency are associated with a greater chance of malignancy; thus, most patients with adrenal tumours will undergo routine genetic testing during their investigations.

Neuroblastomas ( Fig. 20.13 ) ( E-Fig. 20.6 ) are highly malignant embryonal tumours of neuroblasts, typically arising in childhood.

Key to Figures

A adenoma C cortex N hyperplastic nodule

Multiple Endocrine Neoplasia Syndromes

The multiple endocrine neoplasia (MEN) syndromes are a group of inherited conditions characterised by tumours (benign and malignant) of multiple endocrine glands. Whilst the tumours involved may not be unique to MEN, they are distinguished from sporadic lesions by:

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  a younger age at onset

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  tumours preceded by hyperplasia in the gland

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  presentation with multiple organs involved

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  several tumours arising in one organ

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  a more aggressive clinical course.

The main syndromes are MEN-1 and MEN-2 (further subdivided to MEN-2A, MEN-2B and familial medullary thyroid cancer), both of which are inherited in an autosomal dominant manner. In MEN-1 (Werner syndrome), abnormalities of the parathyroid, pancreas and pituitary predominate, whereas in MEN-2A and -2B, phaeochromocytomas and thyroid (medullary carcinoma) tumours are typical, with mucocutaneous neuromas distinguishing MEN-2B.

Key to Figures

G ganglion cell R Homer Wright rosette V vascular channels Z zellballen

Table 20.1

Chapter review.

Disorder	Main features	Figure
Pituitary gland
Pituitary adenoma	Derived from cells of anterior pituitary. May present with endocrine symptoms if hormone secreting. Typically, expanded nests of monotonous cells with moderate amounts of cytoplasm. Immunohistochemistry to identify secreted hormones.	20.1 20.2
Thyroid gland
Hashimoto’s thyroiditis	Autoimmune thyroiditis with destruction of thyroid acini. Inflammatory cell infiltrate in gland with formation of lymphoid follicles.	20.3
Graves’ disease	Autoimmune disease. Commonest cause of pathological thyroid hyperplasia. Triad of hyperthyroidism, exophthalmos, pre-tibial myxoedema. Thyrotoxic hyperplasia with small acini and scalloping of colloid.	20.4
Multinodular goitre	Majority as result of iodine deficiency. Nodules of varying sizes	20.5
Thyroid adenoma	Benign tumours of follicular epithelium. Encapsulated. Solitary. Majority non-functioning.	20.6
Non-invasive follicular patterned neoplasm with papillary-like nuclear features	These are newly described, thyroid lesions that are well circumscribed or encapsulated. They are composed exclusively of thyroid follicles lined by cells that show the typical nuclear features of papillary carcinoma. Molecular profiling of these lesions has shown that they have a similar molecular profile to follicular adenomas and are regarded as indolent.
Papillary carcinoma	Most common thyroid malignancy. Papillary architecture with tumour cells lining stromal cores. Optically clear nuclei (Orphan Annie eye).	20.7A and B
Follicular carcinoma	Solitary, encapsulated or invasive lesions. May be difficult to differentiate from adenoma. Extensive sampling for capsular and/or vascular invasion indicated.	20.7C
Medullary carcinoma	Uncommon tumour of parafollicular cells. Notable for amyloid production.	20.7D
Anaplastic carcinoma	Aggressive, undifferentiated tumour arising in elderly.
Parathyroid glands
Hyperplasia	Increased demand for parathyroid hormone results in expansion of endocrine component. Normally all four glands involved.	20.8B
Adenoma	Benign. Usually only in one of four glands. Adenoma cells replace normal gland architecture. May be surviving rim of normal gland.	20.8C
Carcinoma	Rare. Presents with very high serum calcium. Invasion of the tumour beyond the capsule together with vascular invasion.	20.8D
Adrenal glands
Cortical atrophy	Response to stress or long-term corticosteroid administration.	20.9B
Cortical hyperplasia	May be diffuse or, more commonly, nodular. Diffuse hyperplasia may be response to pituitary or ectopic ACTH. Nodular commonly idiopathic.	20.9C and D
Cortical adenoma	Independent of ACTH secretion. Solitary nodule in cortex, often of multiple cell types. Common incidental finding at autopsy.	20.10
Phaeochromocytoma	Arise from medullary chromaffin cells. Symptoms of catecholamine secretion. Nests ( zellballen ) of plump cells with granular cytoplasm.	20.11
Paraganglioma	Tumour of extra-adrenal paraganglion system. Equivalent of adrenal phaeochromocytoma. Carotid body tumour is one example.	20.12
Neuroblastoma	Adrenal embryonal tumour. Highly malignant. Most common childhood extracranial solid malignancy.	20.13

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