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Dorchester Center, MA 02124
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:
Prolactinomas: secrete prolactin and may lead to infertility and, occasionally, inappropriate breast milk production.
Corticotroph adenomas: secrete adrenocorticotrophic hormone (ACTH) and result in Cushing’s disease ( Fig. 20.1 ).
Thyrotroph and gonadotroph adenomas: both types are rare.
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 .
A pituitary adenoma Ap adenohypophysis Np neurohypophysis
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.
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.
Through the molecular sequencing of a subtype of papillary thyroid carcinoma, known as an encapsulated follicular variant of papillary thyroid carcinoma, it has been possible to reclassify some of these cases. A proportion of these lesions have been shown to have a similar molecular profile to follicular adenomas and are now classified as non-invasive follicular patterned neoplasm with papillary-like nuclear features (NIFTP). These lesions are thought to have benign/indolent behaviour, similar to a follicular adenoma. This is an example of how new technologies can be a useful adjunct to the more traditional histopathology and allied techniques (see Ch. 1 ).
Solitary thyroid nodules (defined as palpable, discrete nodules in an otherwise unremarkable thyroid) are detectable in approximately 5% of the population, the figure increasing with age and higher in women than in men. The differential diagnosis of these solitary nodules is wide and ranges from benign disease (such as thyroiditis or adenoma) to malignant disease (metastatic or primary), though the overwhelming majority are benign. Indications of a more concerning diagnosis may be revealed through careful history taking and/or clinical examination. However, as in many fields of medicine, the clinical clues to differentiate benign from malignant disease are not foolproof and further investigations are often required.
Ultrasound guided fine needle aspiration (FNA) is the most commonly used procedure in investigating solitary thyroid nodules. This is a relatively simple procedure that can be undertaken in the out-patient department. In the majority of cases, the results can provide insight into the nature of the nodule to allow planning of further management. Thus, if the lesion is small and benign, no further action may be indicated. Alternatively, if the lesion is malignant, surgical excision can be planned, with the extent of surgery guided by the nature of the malignancy.
A proportion of lesions will be reported as follicular lesions of uncertain significance. In this setting, molecular profiling tests can be performed on cytology aspirate material to look for high risk molecular signals that would prompt surgical management. If these high risk molecular signals are absent, then the patient can be reassured that the lesion is likely to be benign and no further treatment is required.
A thyroid acini F lymphoid follicle H Hürthle cells P papillary structure S scalloping
A adenoma C capsule F follicular carcinoma N nodule OA Orphan Annie eye nuclei S stromal core Sp spindle cells T surrounding thyroid gland
Molecular pathology is becoming increasingly important in the diagnosis and treatment of thyroid cancer. Up to 80% of papillary thyroid carcinomas show an activating mutation in the BRAF V600E gene, which can be demonstrated by appropriate molecular tests, for example using sequencing.
Other pathways important in thyroid cancer are being investigated including TERT promotor mutations . Drugs that specifically target these mutations are being developed to provide a personalised treatment pathway for thyroid cancer patients.
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 ).
C capsular invasion
The adrenal gland ( Fig. 20.9A ) has two distinct morphological and functional components:
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.
The medulla : This forms part of the neuroendocrine system and is responsible for the production of the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine).
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:
Cushing’s syndrome: caused by cortisol secreting tumours
Conn’s syndrome: resulting from aldosterone secreting tumours
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.
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.
A adenoma C cortex N hyperplastic nodule
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:
a younger age at onset
tumours preceded by hyperplasia in the gland
presentation with multiple organs involved
several tumours arising in one organ
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.
G ganglion cell R Homer Wright rosette V vascular channels Z zellballen
|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
|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.
|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.|
|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|
|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|
An FNA examination is undertaken of a 3 cm lesion within the right lobe of thyroid. Flecks of calcification are seen throughout the gland on ultrasound examination and the ultrasonographer is worried that the lesion might be malignant. An FNA is performed and psammoma bodies are seen together with epithelial cells that contain intranuclear pseudo-inclusions. What is the likely diagnosis?
A patient presents with general lethargy and a goitre. Blood tests show low levels of thyroid stimulating hormones, T3 and T4. A diagnosis of hypothyroidism is made. A biopsy of the thyroid shows lymphocytes and Hürthle cells. What is the likely diagnosis?