Endocrine and Breast Pathology PDF

25 782 The Endocrine System SECTION III 2. Small neuropeptides: gonadotropin-releasing hormone BASIC CONCEPT OF ENDOCRINES...

25 782 The Endocrine System SECTION III 2. Small neuropeptides: gonadotropin-releasing hormone BASIC CONCEPT OF ENDOCRINES (GnRH), thyrotropin-releasing hormone (TRH), somatostatin, The development, structure and functions of human body are vasopressin. Systemic Pathology governed and maintained by 2 mutually interlinked systems— Group II: Those interacting with intracellular nuclear the endocrine system and the nervous system (Chapter 28); receptors: a third system combining features of both these systems is 3. Large proteins: insulin, luteinising hormone (LH), para ­ appropriately called neuroendocrine system. thormone hormone. 4. Steroid hormones: cortisol, estrogen. NEUROENDOCRINE SYSTEM 5. Vitamin derivatives: retinol (vitamin A) and vitamin D. The synthesis of these hormones and their precursors This system forms a link between endocrine glands and takes place through a prescribed genetic pathway that nervous system. The cells of this system elaborate polypeptide involves: transcription → mRNA → protein synthesis → post hormones; owing to these biochemical properties, it has also ­ -translational protein processing → intracellular sorting/ been called as APUD cell system (acronym for Amine Precursor membrane integration → secretion. Uptake and Decarboxylation properties). However, though Major functions of hormones are as under: having common biochemical properties, the cells of this system i) Growth and differentiation of cells: by pituitary hormones, ­ are widely distributed in the body in different anatomic areas; thyroid, parathyroid, steroid hormones. hence it is currently called dispersed neuroendocrine system. ii) Maintenance of homeostasis: by thyroid (by regulating Cells comprising this system are as under: BMR), parathormone, mineralocorticoids, vasopressin, insulin. 1. Neuroendocrine cells which are present in the gastric and iii) Reproduction: sexual development and activity, pregnancy, intestinal mucosa and elaborate peptide hormones. foetal development, menopause etc. 2. Neuroganglia cells lie in the ganglia cells in the sympathetic A basic feature of all endocrine glands is the existence of chain and elaborate amines. ­ both negative and positive feedback control system that 3. Adrenal medulla elaborates epinephrine and norepineph- stimulates or regulates hormone production in a way that rine. levels remain within the normal range (abbreviated as S or 4. Parafollicular C cells of the thyroid secrete calcitonin. R respectively with the corresponding hormone e.g. TSH- 5. Islets of Langerhans in the pancreas (included in both ­ TRH pathway, GnRH-LH/FSH pathway etc). This system is endocrine and neuroendocrine systems) secrete insulin. commonly termed hypothalamic-pituitary hormone axis for 6. Isolated cells in the left atrium of the heart secrete atrial ­ ­ different hormones schematically illustrated in Fig. 25.1. natriuretic (salt-losing) peptide hormone. The stimulatory or regulatory action by endocrine hormonal In addition to above, other non-endocrine secretions secretions may follow paracrine or autocrine pathways: include neurotransmitter substances such as acetylcholine and ” Paracrine regulation means that the stimulatory/regulatory dopamine released from neural synapses, and erythropoietin ” factors are released by one type of cells but act on another and vitamin D3 elaborated from the kidney. adjacent cell of the system. ” Autocrine regulation refers to action of the factor on the THE ENDOCRINE SYSTEM ” same cell that produced it. Anatomically, the endocrine system consists of 6 distinct With this brief overview of principles of physiology of organs: pituitary, adrenals, thyroid, parathyroids, gonads, hormones, we now turn to the study of diseases of the endocrine and pancreatic islets; the last one is included in neuro organs. In general, pathologic processes affecting endocrine ­ endocrine system also). Understanding the pathology of these glands with resultant hormonal abnormalities may occur from endocrine organs requires the knowledge of overall framework following processes: ­ of hormone secretions, their actions and broad principles of Hyperfunction This results from excess of hormone secreting feedback mechanisms. tissues e.g. hyperplasia, tumours (adenoma, carcinoma), Broadly speaking, human hormones are divided into 5 ectopic hormone production, excessive stimulation from major classes which are further grouped under two headings inflammation (often autoimmune), infections, iatrogenic depending upon their site of interactions on the target cell (drugs-induced, hormonal administration). receptors (whether cell membrane or nuclear receptor): Hypofunction Deficiency of hormones occurs from destruc ­ Group I: Those interacting with cell-surface membrane tion of hormone-forming tissues from inflammation (often receptors: autoimmune), infections, iatrogenic (e.g. surgical removal, 1. Amino acid derivatives: thyroid hormone, catecholamines. radiation damage), developmental defects (e.g. Turner’s ­ ­ tahir99 - UnitedVRG - vip.persianss.ir  783 CHAPTER 25 The Endocrine System Figure 25.1 Endocrine organs and the presence of feedback controls. Both positive and negative feedback controls exist for each endocrine gland having a regulating (R) and stimulating (S) hormone. Those acting through hypothalamic-pituitary axis include: thyroid hormones on TRH-TSH axis, cortisol on CRH-ACTH axis, gonadal steroids on GnRH-LH/FSH axis and insulin-like GH on GHRH-GH axis. Those independent of pituitary control (shown by interrupted arrows) have also feedback controls by calcium on PTH, and hypoglycaemia on insulin release by pancreatic islets. syndrome, hypoplasia), enzyme deficiency, haemorrhage and Œ These include neuroendocrine cells in gastric and infarction (e.g. Sheehan’s syndrome), nutritional deficiency Œ intestinal mucosa, neuroganglia cells, adrenal medulla, (e.g. iodine deficiency). parafollicular C cells of the thyroid, islets of Langerhans Hormone resistance There may be adequate or excessive pro and isolated cells in the left atrium. ­ duction of a hormone but there is peripheral resistance, often Œ Anatomically, endocrine system consists of 6 distinct ­ Œ from inherited mutations in receptors (e.g. defect in membrane organs: pituitary, adrenals, thyroid, parathyroids, gonads, receptors, nuclear receptors or receptor for signal transduction). and pancreatic islets. Œ A basic feature of all endocrine glands is the existence of Œ ­ GIST BOX 25.1 Miscelaneous Endocrine Tumours both negative and positive feedback control system that stimulates or regulates hormone production in a way that Œ Neuroendocrine system forms a link between endocrine levels remain within the normal range. Œ glands and nervous system. The cells comprising this Œ Diseases of endocrine glands occur due to their hyper- Œ system lie at different places in the body, hence called or hypo- function or from peripheral resistance of the dispersed neuroendocrine system. hormone. tahir99 - UnitedVRG - vip.persianss.ir  These nerve fibres on electron microscopy contain granules 784 PITUITARY GLAND of neurosecretory material made up of 2 octapeptides— NORMAL STRUCTURE vasopressin or antidiuretic hormone (ADH), and oxytocin, both of which are produced by neurosecretory cells of the ­ ANATOMY The pituitary gland or hypophysis in an adult hypothalamus but are stored in the cells of posterior pituitary. SECTION III 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 1. ADH It causes reabsorption of water from the renal tubules formed out of the sphenoid bone. The gland is composed of 2 and is essential for maintenance of osmolality of the plasma. major anatomic divisions: anterior lobe (adenohypophysis) Its deficiency results in diabetes insipidus characterised by and posterior lobe (neurohypophysis). uncontrolled diuresis and polydipsia. ” The anterior lobe or adenohypophysis is an ecto 2. Oxytocin It causes contraction of mammary myoepithe ” ­ ­ ­ dermal derivative formed from Rathke’s pouch which is an lial cells resulting in ejection of milk from the lactating breast upward diverticulum from the primitive buccal cavity. The and causes contraction of myometrium of the uterus at term. adenohypophysis has no direct neural connection but has It is obvious from the description above that pituitary, Systemic Pathology ­ indirect connection through capillary portal circulation by though a tiny organ, is concerned with a variety of diverse which the anterior pituitary receives the blood which has functions in the body. The pituitary gland and hypothalamus already passed through the hypothalamus. are so closely interlinked that diseases of the pituitary ” The posterior lobe or neurohypophysis is a down gland involve the hypothalamus, and dysfunctions of the ­ ” ­ growth from the primitive neural tissue. The neurohypophysis, ­ hypothalamus cause secondary changes in the pituitary. The therefore, has direct neural connection superiorly with the pituitary gland is involved in several diseases which include: ­ hypothalamus. non-neoplastic (e.g. inflammations, haemorrhage, trauma, infarction and many other endocrine diseases) and neoplastic HISTOLOGY AND FUNCTIONS The histology and functions diseases. However, functionally and morphologically, diseases of the anterior and posterior lobes of the pituitary gland are ­ of the pituitary can be classified as below, each of which quite distinct. ­ includes diseases of the anterior and posterior pituitary and ­ A. ANTERIOR LOBE (ADENOHYPOPHYSIS) It is com the hypothalamus, separately: ­ posed of round to polygonal epithelial cells arranged in cords i) Hyperpituitarism and islands having fibrovascular stroma. These epithelial cells, ii) Hypopituitarism depending upon their staining characteristics and functions, iii) Pituitary tumours are divided into 3 types, each of which performs separate functions: HYPERPITUITARISM 1. Chromophil cells with acidophilic granules These cells Hyperpituitarism is characterised by oversecretion of one comprise about 40% of the anterior lobe and are chiefly located or more of the pituitary hormones. Such hypersecretion in the lateral wings. The acidophils are further of 2 types: ­ ­ may be due to diseases of the anterior pituitary, posterior i) Somatotrophs (GH cells) which produce growth hormone ­ pituitary or hypothalamus. For all practical purposes, (GH). ­ however, hyperfunction of the anterior pituitary is due to ii) Lactotrophs (PRL cells) which produce prolactin (PRL). ­ the development of a hormone-secreting pituitary adenoma Cells containing both GH and PRL called mammo ­ (discussed later), and rarely, a carcinoma. For each of the ­ somatotrophs are also present. ­ hormonal hyperfunction of the anterior pituitary, posterior 2. Chromophil cells with basophilic granules These cells pituitary and hypothalamus, a clinical syndrome is described. ­ ­ ­ constitute about 10% of the anterior lobe and are mainly found A few important syndromes are as follows: in the region of median wedge. The chromatophils include 3 types of cells: A. HYPERFUNCTION OF ANTERIOR PITUITARY i) Gonadotrophs (FSH-LH cells) which are the source of the FSH and LH or interstitial cell stimulating hormone (ICSH). Three common syndromes of adenohypophyseal hyper ­ ii) Thyrotrophs (TSH cells) are the cells producing TSH. function are: gigantism and acromegaly, hyperprolactinaemia ­ iii) Corticotrophs (ACTH-MSH cells) produce ACTH, and Cushing’s syndrome. melanocyte stimulating hormone (MSH), β-lipoprotein and GIGANTISM AND ACROMEGALY Both these clinical synd ­ β-endorphin. romes result from sustained excess of growth hormone (GH), 3. Chromophobe cells without visible granules These most commonly by somatotroph (GH-secreting) adenoma. cells comprise the remainder 50% of the adenohypophysis. Gigantism When GH excess occurs prior to epiphyseal ­ ­ These cells by light microscopy contain no visible granules, closure, gigantism is produced. Gigantism, therefore, occurs ­ but on electron microscopy reveal sparsely granulated cortico in prepubertal boys and girls and is much less frequent than ­ trophs, thyrotrophs and gonadotrophs. acromegaly. The main clinical feature in gigantism is the ­ All these functions of the adenohypophysis are under the ­ excessive and proportionate growth of the child. There is indirect control of the hypothalamus through stimulatory and enlargement as well as thickening of the bones resulting in inhibitory factors synthesised by the hypothalamus which considerable increase in height and enlarged thoracic cage. reach the anterior lobe through capillary portal blood. Acromegaly Acromegaly results when there is overproduc ­ ­ B. POSTERIOR LOBE (NEUROHYPOPHYSIS) The neuro tion of GH in adults following cessation of bone growth and is ­ hypophysis is composed mainly of interlacing nerve fibres more common than gigantism. The term ‘acromegaly’ means ­ in which are scattered specialised glial cells called pituicytes. increased growth of extremities (acro=extremity). There is tahir99 - UnitedVRG - vip.persianss.ir enlargement of hands and feet, coarseness of facial features A. HYPOFUNCTION OF ANTERIOR PITUITARY 785 with increase in soft tissues, prominent supraorbital ridges Adenohypophyseal hypofunction is invariably due to and a more prominent lower jaw which when clenched destruction of the anterior lobe of more than 75% because results in protrusion of the lower teeth in front of upper the anterior pituitary possesses a large functional reserve. CHAPTER 25 teeth (prognathism). Other features include enlargement ­ This may result from anterior pituitary lesions or pressure of the tongue and lips, thickening of the skin and kyphosis. ­ and destruction from adjacent lesions. Lesions of the Sometimes, a few associated features such as TSH excess anterior pituitary include nonsecretory (chromophobe) resulting in thyrotoxicosis, and gonadotropin insufficiency adenoma, metastatic carcinoma, craniopharyngioma, trauma, causing amenorrhoea in the females and impotence in the postpartum ischaemic necrosis (Sheehan’s syndrome), empty- male, are found. sella syndrome, and rarely, tuberculosis. Though a number PROLACTINAEMIA Prolactinaemia is lactotroph (PRL- of syndromes associated with deficiency of anterior pituitary ­ secreting) pituitary adenoma, also called prolactinoma hormones have been described, two important syndromes are ­ having excessive production of prolactin. Occasionally, panhypopituitarism and dwarfism. The Endocrine System hyperprolactinaemia results from hypothalamic inhibition of PANHYPOPITUITARISM The classical clinical condition PRL secretion by certain drugs (e.g. chlorpromazine, reserpine of major anterior pituitary insufficiency is called panhypo and methyl-dopa). In the female, hyperprolactinaemia causes ­ pituitarism. Three most common causes of panhypopituitarism amenorrhoea-galactorrhoea syndrome characterised clinically ­ are: non-secretory (chromophobe) adenoma (discussed later), by infertility and expression of a drop or two of milk from ­ Sheehan’s syndrome and Simmond’s disease, and empty-sella breast, not related to pregnancy or puerperium. In the male, syndrome. ­ it may cause impotence or reduced libido. These features result either from associated inhibition of gonadotropin secretion or Sheehan’s syndrome and Simmond’s disease Pituitary ­ interference in gonadotropin effects. insufficiency occurring due to postpartum pituitary (Sheehan’s) ­ ­ necrosis is called Sheehan’s syndrome, whereas occurrence CUSHING’S SYNDROME Pituitary-dependent Cushing’s of similar process without preceding pregnancy as well as its syndrome results from ACTH excess. Most frequently, it is ­ occurrence in males is termed Simmond’s disease. The main caused by corticotroph (ACTH-secreting) adenoma. Cushing’s pathogenetic mechanism underlying Sheehan’s necrosis is the syndrome is discussed under diseases of the adrenal gland on ­ enlargement of the pituitary occurring during pregnancy which page 788. ­ ­ may be followed by hypotensive shock precipitating ischaemic necrosis of the pituitary. Other mechanisms hypothesised B. HYPERFUNCTION OF POSTERIOR PITUITARY AND are: DIC following delivery, traumatic injury to vessels, and   HYPOTHALAMUS excessive haemorrhage. Patients with long-standing diabetes Lesions of posterior pituitary and hypothalamus are mellitus appear to be at greater risk of developing this uncommon. Two of the syndromes associated with hyper complication. ­­­ function of the posterior pituitary and hypothalamus are: The first clinical manifestation of Sheehan’s syndrome ­ inappropriate release of ADH and precocious puberty. is failure of lactation following delivery which is due to deficiency of prolactin. Subsequently, other symptoms develop INAPPROPRIATE RELEASE OF ADH Inappropriate release which include loss of axillary and pubic hair, amenorrhoea, ­ of ADH results in its excessive secretion which manifests sterility and loss of libido. Concomitant deficiency of TSH clinically by passage of concentrated urine due to increased ­ and ACTH may result in hypothyroidism and adrenocortical reabsorption of water and loss of sodium in the urine, ­ ­ insufficiency. consequent hyponatraemia, haemodilution and expansion of intra- and extracellular fluid volume. Inappropriate release MORPHOLOGIC FEATURES Sheehan’s syndrome of ADH occurs most often in paraneoplastic syndrome during early stage shows ischaemic necrosis and e.g. in oat cell carcinoma of the lung, carcinoma of the pan haemorrhage in the anterior pituitary, while later necrotic ­ ­ creas, lymphoma and thymoma. Infrequently, lesions of the tissue is replaced by fibrous tissue. hypothalamus such as trauma, haemorrhage and meningitis may produce ADH hypersecretion. Rarely, pulmonary diseases Empty-sella syndrome Empty-sella syndrome is charac such as tuberculosis, lung abscess, pneumoconiosis, empyema ­ terised by the appearance of an empty sella and features and pneumonia may cause overproduction of ADH. of panhypopituitarism. Most commonly, it results from PRECOCIOUS PUBERTY A tumour in the region of herniation of subarachnoid space into the sella turcica due hypothalamus or the pineal gland may result in premature to an incomplete diaphragma sella creating an empty sella. ­­ ­ release of gonadotropins causing the onset of pubertal changes Other less common causes are Sheehan’s syndrome, infarction prior to the age of 9 years. The features include premature and scarring in an adenoma, irradiation damage, or surgical development of genitalia both in the male and in the female, removal of the gland. growth of pubic hair and axillary hair. In the female, there is PITUITARY DWARFISM Severe deficiency of GH in breast growth and onset of menstruation. children before growth is completed results in retarded growth and pituitary dwarfism. Most commonly, isolated GH HYPOPITUITARISM ­ deficiency is the result of an inherited autosomal recessive In hypopituitarism, there is usually deficiency of one or more disorder. Less often, it may be due to a pituitary adenoma or of the pituitary hormones affecting either anterior pituitary, or craniopharyngioma, infarction and trauma to the pituitary. ­ ­ posterior pituitary and hypothalamus. The clinical features of inherited cases of pituitary dwarfism tahir99 - UnitedVRG - vip.persianss.ir 786 appear after one year of age. These include proportionate PITUITARY ADENOMAS retardation in growth of bones, normal mental state for age, ­ Adenomas are the most common pituitary tumours. They poorly-developed genitalia, delayed puberty and episodes of are conventionally classified according to their H & E hypoglycaemia. Pituitary dwarf must be distinguished from staining characteristics of granules into acidophil, basophil hypothyroid dwarf (cretinism) in which there is achondroplasia SECTION III and chromophobe adenomas. However, this morphologic and mental retardation (page 794). classification is considered quite inadequate because of the significant functional characteristics of each type of adenoma B. HYPOFUNCTION OF POSTERIOR PITUITARY including the chromophobe adenoma, which on H & E staining   AND HYPOTHALAMUS does not show visible granules. As a result of advances in the Insufficiency of the posterior pituitary and hypothalamus is ultrastructural and immunocytochemical studies, a functional ­ uncommon. The only significant clinical syndrome due to classification of pituitary adenoma has emerged. Table 25.1 ­ hypofunction of the neurohypophysis and hypothalamus is presents a classification of pituitary adenomas based on ­ diabetes insipidus. functional features as correlated with morphologic features of Systemic Pathology older classification. The syndromes produced by the tumours DIABETES INSIPIDUS Deficient secretion of ADH causes have been described already. diabetes insipidus. The causes of ADH deficiency are: inflammatory and neoplastic lesions of the hypothalamo- hypophyseal axis, destruction of neurohypophysis due to MORPHOLOGIC FEATURES Grossly, pituitary surgery, radiation, head injury, and lastly, are those cases where adenomas range in size from small foci of less than 10 mm no definite cause is known and are labelled as idiopathic. The in size (termed microadenoma) to large adenomas several main features of diabetes insipidus are excretion of a very large centimeters in diameter (> 1 cm called macroadenomas). They are spherical, soft and encapsulated. ­ volume of dilute urine of low specific gravity (below 1.010), ­ polyuria and polydipsia. Histologically, by light microscopy of H & E stained ­ sections, an adenoma is composed predominantly of one of PITUITARY TUMOURS the normal cell types of the anterior pituitary i.e. acidophil, basophil or chromophobe cells. These cells may have Tumours of the anterior pituitary are more common than following 3 types of patterns: those of the posterior pituitary and hypothalamus. The most 1. Diffuse pattern is composed of polygonal cells arranged in common of the anterior pituitary tumours are adenomas; sheets with scanty stroma. primary and metastatic carcinomas being rare. Craniopharyn 2. Sinusoidal pattern consists of columnar or fusiform cells ­ ­ gioma and granular cell tumour (choristoma) are the other with fibrovascular stroma around which the tumour cells benign pituitary tumours found occasionally. are arranged (Fig. 25.2). All pituitary tumours, whether benign or malignant, cause 3. Papillary pattern is composed of columnar or fusiform symptoms by following 2 ways: cells arranged about fibrovascular papillae. 1. Pressure effects These are caused by expansion of the lesion resulting in destruction of the surrounding Functionally, most common pituitary adenomas, glandular tissue by pressure atrophy. This causes erosion and in decreasing order of frequency, are: lactotroph (PRL- enlargement of sella turcica, upward extension of the tumour secreting) adenoma, somatotroph (GH-secreting) adenoma ­ damaging the optic chiasma, optic nerves, neurohypophysis and corticotroph (ACTH-secreting) adenoma. Infrequently, and adjacent cranial nerves, and rarely, downward extension mixed somatotroph-lactotroph (GH-PRL-secreting) adenoma, into the nasopharynx. gonadotroph (FSH-LH-secreting) adenomas and null-cell 2. Hormonal effects Depending upon their cell types, (endocrinologically inactive) adenomas or oncocytoma are pituitary adenomas produce excess of pituitary hormones and found. Pleurihormonal-pituitary adenoma, on the other ­ the corresponding clinical syndromes of hyperpituitarism. hand, may have multiple hormone elaborations. Functional ­ Infarction and destruction of adenoma may cause symptoms classification of pituitary adenoma can be done by carrying out of hypopituitarism. specific immunostains against the hormone products. Table 25.1 Morphologic and functional classification of pituitary adenomas. FUNCTIONAL TYPE FREQUENCY HORMONES PRODUCED CLINICAL SYNDROME 1. Lactotroph adenoma (Prolactinoma) 20-30% PRL Hypogonadism, galactorrhoea 2. Somatotroph adenoma 5% GH Acromegaly/gigantism 3. Mixed somatotroph-lactotroph adenoma 5% PRL, GH Acromegaly, hypogonadism, galactorrhoea 4. Corticotroph adenoma 10-15% ACTH Cushing’s syndrome 5. Gonadotroph adenoma 10-15% FSH-LH Inactive or hypogonadism 6. Thyrotroph adenoma 1% TSH Thyrotoxicosis 7. Null cell adenoma/ oncocytoma 20% Nil Pituitary failure 8. Pleurihormonal adenoma 15% Multiple hormones Mixed tahir99 - UnitedVRG - vip.persianss.ir  Œ In hypopituitarism, there is usually deficiency of one or 787 Œ more of the pituitary hormones affecting either anterior ­ pituitary (e.g. Sheehan’s syndrome, empty sella syndrome, dwarfism), or posterior pituitary and hypothalamus (e.g. CHAPTER 25 diabetes insipidus). Œ Major pituitary tumours are adenomas (micro- and Œ macroadenomas) and craniopharyngioma. ADRENAL GLAND NORMAL STRUCTURE ANATOMY The adrenal glands lie at the upper pole of each The Endocrine System kidney. Each gland weighs approximately 4 gm in the adult but in children the adrenals are proportionately larger. On sectioning, the adrenal is composed of 2 distinct parts: an outer yellow-brown cortex and an inner grey medulla. The anatomic and functional integrity of adrenal cortices are essential for life, while it does not hold true for adrenal medulla. Figure 25.2 Pituitary adenoma, sinusoidal pattern. HISTOLOGY AND PHYSIOLOGY Microscopically and functionally, cortex and medulla are quite distinct. ADRENAL CORTEX It is composed of 3 layers: Pituitary adenomas occur in the age group of 3rd to 6th decade of life. They are mostly sporadiac. Less than 5% are 1. Zona glomerulosa is the outer layer and comprises about familial having germline mutation in MEN1 gene. The latter 10% of the cortex. It consists of cords or columns of polyhedral cases occur as a part of multiple endocrine neoplasia type I cells just under the capsule. This layer is responsible for the (MEN-I) in which pituitary adenoma is associated with synthesis of mineralocorticoids, the most important of which is adenomas of pancreatic islets and parathyroids (page 819). aldosterone, the salt and water regulating hormone. ­ Sporadiac cases appear to be due to genetic abnormalities of 2. Zona fasciculata is the middle layer and constitutes signaling pathways, particularly G protein mutations. approximately 70% of the cortex. It is composed of columns of Clinically, patients of pituitary adenomas generally have lipid-rich cells which are precursors of various steroid hormones combination of features of Zollinger-Ellison’s syndrome, manufactured in the adrenal cortex such as glucocorticoids hyperparathyroidism and hyperpituitarism. (e.g. cortisol) and sex steroids (e.g. testosterone). ­ ­ CRANIOPHARYNGIOMA 3. Zona reticularis is the inner layer which makes up the remainder of the adrenal cortex. It consists of cords of more Craniopharyngioma is a benign tumour arising from remnants compact cells than those of zona fasciculata but has similar of Rathke’s pouch. It has 2 peaks of occurrence: children and functional characteristics of synthesis and secretion of young adults in 1st to 2nd decade and then in adults past 6th glucocorticoids and androgens. decade. The tumour, though benign, compresses as well as The synthesis of glucocorticoids and adrenal androgens invades the adjacent structures extensively. ­ is under the control of ACTH from hypothalamus-anterior ­ pituitary. In turn, ACTH release is under the control of a MORPHOLOGIC FEATURES Grossly, the tumour is hypothalamic releasing factor called corticotropin-releasing encapsulated, adherent to surrounding structures and is ­ factor. Release of aldosterone, on the other hand, is independent typically cystic, reddish-grey mass. The fluid in the cystic of ACTH control and is largely regulated by the serum levels of cavity typically has colour and consistency of machinery oil. potassium and renin-angiotensin mechanism (page 83). Histologically, craniopharyngioma closely resembles ameloblastoma of the jaw (page 513). There are 2 distinct ADRENAL MEDULLA The adrenal medulla is a compo ­ histologic features: nent of the dispersed neuroendocrine system derived from ­ 1. Stratified squamous epithelium frequently lining a cyst primitive neuroectoderm; the other components of this system ­ and containing loose stellate cells in the centre. being paraganglia distributed in the vagi, paravertebral and 2. Solid ameloblastic areas. visceral autonomic ganglia. The cells comprising this system are neuroendocrine cells, the major function of which is ­ synthesis and secretion of catecholamines (epinephrine and GIST BOX 25.2 Diseases of Pituitary Gland norepinephrine). Various other peptides such as calcitonin, somatostatin and vasoactive intestinal polypeptide (VIP) Œ Hyperpituitarism is oversecretion of one or more of the ­ are also secreted by these cells. The major metabolites of Œ pituitary hormones due to diseases of the anterior pitui catecholamines are metanephrine, nor-metanephrine, vanillyl ­ tary (e.g. gigantism, acromegaly, prolactinoma, Cushing’s ­ mandelic acid (VMA) and homovanillic acid (HVA). In case of syndrome), posterior pituitary or hypothalamus (e.g. ­ damage to the adrenal medulla, its function is taken over by inappropriate release of ADH, precocious puberty). other paraganglia. tahir99 - UnitedVRG - vip.persianss.ir 788 Diseases affecting the two parts of adrenal glands are 4. Iatrogenic Cushing’s syndrome Prolonged therapeutic ­ quite distinctive in view of distinct morphology and function administration of high doses of glucocorticoids or ACTH may of the adrenal cortex and medulla. While the disorders of result in Cushing’s syndrome e.g. in organ transplant recipients the adrenal cortex include adrenocortical hyperfunction and in autoimmune diseases. These cases are generally (hyperadrenalism), adrenocortical insufficiency (hypoadrena associated with bilateral adrenocortical insufficiency. SECTION III ­ ­ lism) and adrenocortical tumours, the main lesions affecting CLINICAL FEATURES Cushing’s syndrome occurs more the adrenal medulla are the medullary tumours. often in patients between the age of 20-40 years with three times higher frequency in women than in men. The severity of ADRENOCORTICAL HYPERFUNCTION the syndrome varies considerably, but in general the following (HYPERADRENALISM) features characterise a case of Cushing’s syndrome: Hypersecretion of each of the three types of corticosteroids 1. Central or truncal obesity contrasted with relatively thin ­ elaborated by the adrenal cortex causes distinct corresponding arms and legs, buffalo hump due to prominence of fat over the hyperadrenal clinical syndromes: shoulders, and rounded oedematous moon-face. Systemic Pathology 1. Cushing’s syndrome caused by excess of glucocorticoids 2. Increased protein breakdown resulting in wasting and ­ ­ (i.e. cortisol); also called chronic hypercortisolism. thinning of the skeletal muscles, atrophy of the skin and ­ 2. Conn’s syndrome caused by oversecretion of mineralo subcutaneous tissue with formation of purple striae on the ­­ corticoids (i.e. aldosterone); also called primary hyper abdominal wall, osteoporosis and easy bruising of the thin skin ­ aldosteronism. from minor trauma. 3. Adrenogenital syndrome characterised by excessive 3. Systemic hypertension is present in 80% of cases because of production of adrenal sex steroids (i.e. androgens); also called associated retention of sodium and water. ­ adrenal virilism. 4. Impaired glucose tolerance and diabetes mellitus are found Mixed forms of these clinical syndromes may also occur. in about 20% cases. 5. Amenorrhoea, hirsutism and infertility in many women. CUSHING’S SYNDROME (CHRONIC HYPERCORTISOLISM) 6. Insomnia, depression, confusion and psychosis. Cushing’s syndrome is caused by excessive production of cortisol of whatever cause. The full clinical expression of the CONN’S SYNDROME (PRIMARY HYPERALDOSTERONISM) syndrome, however, includes contribution of the secondary This is an uncommon syndrome occurring due to overpro ­ derangements. duction of aldosterone, the potent salt-retaining hormone. ETIOPATHOGENESIS There are 4 major etiologic types ETIOPATHOGENESIS The condition results primarily due to of Cushing’s syndrome which should be distinguished for adrenocortical diseases as follows: effective treatment. 1. Adrenocortical adenoma, producing aldosterone. 1. Pituitary Cushing’s syndrome About 60-70% cases 2. Bilateral adrenal hyperplasia, especially in children of Cushing’s syndrome are caused by excessive secretion (congenital hyperaldosteronism). of ACTH due to a lesion in the pituitary gland, most 3. Rarely, adrenal carcinoma. commonly a corticotroph adenoma or multiple corticotroph ” Primary hyperaldosteronism from any of the above causes microadenomas. This group of cases was first described by ” is associated with low plasma renin levels. Harvey Cushing, an American neurosurgeon, who termed the condition as Cushing’s disease. Also included in this group ” Secondary hyperaldosteronism, on the contrary, occurs in ” are cases with hypothalamic origin of excessive ACTH levels response to high plasma renin level due to overproduction of ­ ­ without apparent pituitary lesion. All cases with pituitary renin by the kidneys such as in renal ischaemia, reninoma or ­ Cushing’s syndrome are characterised by bilateral adrenal oedema. cortical hyperplasia and elevated ACTH levels. These cases CLINICAL FEATURES Conn’s syndrome is more frequent in show therapeutic response on administration of high doses of adult females. Its principal features are as under: ­ dexamethasone which suppresses ACTH secretion and causes 1. Hypertension, usually mild to moderate diastolic hyper ­ ­ fall in plasma cortisol level. tension. 2. Adrenal Cushing’s syndrome Approximately 20-25% 2. Hypokalaemia and associated muscular weakness, cases of Cushing’s syndrome are caused by disease in one peripheral neuropathy and cardiac arrhythmias. or both the adrenal glands. These include adrenal cortical 3. Retention of sodium and water. adenoma, carcinoma, and less often, cortical hyperplasia. This 4. Polyuria and polydipsia due to reduced concentrating ­ ­ group of cases is characterised by low serum ACTH levels and power of the renal tubules. absence of therapeutic response to administration of high ­ doses of glucocorticoid. ADRENOGENITAL SYNDROME (ADRENAL VIRILISM) 3. Ectopic Cushing’s syndrome About 10-15% cases of Adrenal cortex secretes a smaller amount of sex steroids than Cushing’s syndrome have an origin in ectopic ACTH elabo the gonads. However, adrenocortical hyperfunction may ­ ration by non-endocrine tumours. Most often, the tumour occasionally cause sexual disturbances. is small cell carcinoma of the lung but other lung cancers, malignant thymoma and pancreatic tumours have also been ETIOPATHOGENESIS Hypersecretion of sex steroids, mainly implicated. The plasma ACTH level is high in these cases androgens, may occur in children or in adults: and cortisol secretion is not suppressed by dexamethasone ” In children, it is due to congenital adrenal hyperplasia in ” administration. which there is congenital deficiency of a specific enzyme. tahir99 - UnitedVRG - vip.persianss.ir ” In adults, it is caused by an adrenocortical adenoma or a 2. Deficiency of glucocorticoids (i.e. cortisol deficiency) leads 789 ” carcinoma. Cushing’s syndrome is often present as well. to hypoglycaemia, increased insulin sensitivity and vomitings. CLINICAL FEATURES The clinical features depend upon the B. Primary Chronic Adrenocortical Insufficiency age and sex of the patient. CHAPTER 25   (Addison’s Disease) ” In children, there is distortion of the external genitalia in ” girls, and precocious puberty in boys. Progressive chronic destruction of more than 90% of adrenal cortex on both sides results in an uncommon clinical condition ” In adults, the features in females show virilisation (e.g. called Addison’s disease. ” hirsutism, oligomenorrhoea, deepening of voice, hypertrophy ­ of the clitoris); and in males may rarely cause feminisation. ETIOPATHOGENESIS Any condition which causes marked There is generally increased excretion of 17-ketosteroids in chronic adrenal destruction may produce Addison’s disease. ­ the urine. These include: tuberculosis, autoimmune or idiopathic ­ adrenalitis, histoplasmosis, amyloidosis, metastatic cancer, sarcoidosis and haemochromatosis. However, currently the The Endocrine System ADRENOCORTICAL INSUFFICIENCY ­ first two causes—tuberculosis and autoimmune chronic (HYPOADRENALISM) destruction of adrenal glands, are implicated in majority Adrenocortical insufficiency may result from deficient of cases of Addison’s disease. Irrespective of the cause, the synthesis of cortical steroids from the adrenal cortex or may be adrenal glands are bilaterally small and irregularly shrunken. secondary to ACTH deficiency. Three types of adrenocortical Histologic changes, depending upon the cause, may reveal hypofunction are distinguished: specific features as in tuberculosis and histoplasmosis, or ­ 1. Primary adrenocortical insufficiency caused primarily by the changes may be in the form of nonspecific lymphocytic the disease of the adrenal glands. Two forms are described: infiltrate as in idiopathic (autoimmune) adrenalitis. ­ ­ acute or ‘adrenal crisis’, and chronic or ‘Addison’s disease’. CLINICAL FEATURES Clinical manifestations develop 2. Secondary adrenocortical insufficiency resulting from slowly and insidiously. The usual features are as under: diminished secretion of ACTH. 1. Asthenia i.e. progressive weakness, weight loss and lethargy 3. Hypoaldosteronism characterised by deficient secretion of as the cardinal symptoms. aldosterone. 2. Hyperpigmentation, initially most marked on expo ­ sed areas, but later involves unexposed parts and mucous PRIMARY ADRENOCORTICAL INSUFFICIENCY membranes as well. Primary adrenal hypofunction occurs due to defect in the 3. Arterial hypotension. adrenal glands and normal pituitary function. It may develop 4. Vague upper gastrointestinal symptoms such as mild loss of in 2 ways: appetite, nausea, vomiting and upper abdominal pain. A. Acute primary adrenocortical insufficiency or ‘adrenal 5. Lack of androgen causing loss of hair in women. crisis’. 6. Episodes of hypoglycaemia. B. Chronic primary adrenocortical insufficiency or ‘Addison’s 7. Biochemical changes include reduced GFR, acidosis, disease’. hyperkalaemia and low levels of serum sodium, chloride and bicarbonate. A. Primary Acute Adrenocortical Insufficiency   (Adrenal Crisis) SECONDARY ADRENOCORTICAL INSUFFICIENCY Sudden loss of adrenocortical function may result in an acute Adrenocortical insufficiency resulting from deficiency of ACTH condition called adrenal crisis. is called secondary adrenocortical insufficiency. ETIOPATHOGENESIS Causes of acute insufficiency are as ETIOPATHOGENESIS ACTH deficiency may appear in 2 under: settings : 1. Bilateral adrenalectomy e.g. in the treatment of cortical 1. Selective ACTH deficiency due to prolonged administration ­ ­ hyperfunction, hypertension and in selected cases of breast of high doses of glucocorticoids. This leads to suppression cancer. of ACTH release from the pituitary gland and selective 2. Septicaemia e.g. in endotoxic shock and meningococcal deficiency. ­ infection producing grossly haemorrhagic and necrotic 2. Panhypopituitarism due to hypothalamus-pituitary adrenal cortex termed adrenal apoplexy. The acute condition diseases is associated with deficiency of multiple trophic so produced is called Waterhouse-Friderichsen’s syndrome. hormones (page 785). 3. Rapid withdrawal of steroids. CLINICAL FEATURES The clinical features of secondary 4. Any form of acute stress in a case of chronic insufficiency adrenocortical insufficiency are like those of Addison’s disease ­ i.e. in Addison’s disease. except the following: CLINICAL FEATURES Clinical features of acute adreno 1. These cases lack hyperpigmentation because of suppressed ­ cortical insufficiency are due to deficiency of mineralo production of melanocyte-stimulating hormone (MSH) from ­ corticoids and glucocorticoids. These are as follows: the pituitary. 1. Deficiency of mineralocorticoids (i.e. aldosterone defi 2. Plasma ACTH levels are low-to-absent in secondary ­ ciency) result in salt deficiency, hyperkalaemia and dehydra insufficiency but are elevated in Addison’s disease. ­ tion. 3. Aldosterone levels are normal due to stimulation by renin. tahir99 - UnitedVRG - vip.persianss.ir 790 HYPOALDOSTERONISM anaplastic carcinoma shows large, pleomorphic and bizarre Isolated deficiency of aldosterone with normal cortisol level cells with high mitotic activity. may occur in association with reduced renin secretion. MEDULLARY TUMOURS SECTION III ETIOPATHOGENESIS The causes of such hyporeninism are ­ as follows: The most significant lesions of the adrenal medulla are 1. Congenital defect due to deficiency of an enzyme required neoplasms. These include the following: for its synthesis. 1. Benign tumours: These are less common and include 2. Prolonged administration of heparin. pheochromocytoma and myelolipoma. 3. Certain diseases of the brain. 2. Tumours arising from embryonic nerve cells: These are more 4. Excision of an aldosterone-secreting tumour. common and include neuroblastoma and ganglioneuroma. CLINICAL FEATURES The patients of isolated hypo These tumours together with extra-adrenal paraganglioma ­ ­ aldosteronism are adults with mild renal failure and diabetes are described below. Systemic Pathology mellitus. The predominant features are hyperkalaemia and metabolic acidosis. Pheochromocytoma (Chromaffin Tumour) TUMOURS OF ADRENAL GLANDS Pheochromocytoma is a tumour arising from pheochromocytes (i.e. chromaffin cells) of the adrenal medulla. Its name is Primary tumours of the adrenal glands are uncommon and derived from its characteristic dark brown black appearance of include distinct adrenocortical tumours and medullary this tumour caused by chromaffin oxidation of catecholamines. tumours. However, adrenal gland is a more common site for The extra-adrenal pheochromocytomas arising from other metastatic carcinoma. paraganglia are preferably called paragangliomas, named ­ along with the anatomic site of origin, as described later. The ADRENOCORTICAL TUMOURS etiology of these tumours remains unknown but a quarter of cases have inherited germline mutation in RET, VHL, NF1, Cortical Adenoma SDHD, SDHC or SDHS genes. The commonest cortical tumour is adenoma. They are Pheochromocytoma may occur at any age but most patients indistinguishable from hyperplastic nodules except that lesions are 20-60 years old. Most pheochromocytomas are slow-growing smaller than 2 cm diameter are labelled hyperplastic nodules. and benign but about 10% of the tumours are malignant, invasive A cortical adenoma is a benign and slow-growing tumour. It is and metastasising. These tumours are commonly sporadic but usually small and nonfunctional. A few large adenomas may, 10% are associated with familial syndromes of multiple endo ­ however, produce excess of cortisol, aldosterone or androgen. crine neoplasia (MEN) having bilaterality and association with Association of cortical adenomas with systemic hypertension medullary carcinoma of the thyroid, hyperparathyroidism, ­ has been suggested by some workers. Occasionally, a cortical pituitary adenoma, mucosal neuromas and von Recklinghausen’s adenoma may be a part of multiple endocrine neoplasia type I neurofibromatosis in varying combinations. Thus, the traditional (MEN-I) in which patients have associated adenomas of para “10% rule” for pheochromocytoma is 10% familial, 10% ­ thyroid, islet cells and anterior pituitary (page 819). malignant, 10% extra-adrenal. However, currently, malignant pheochromocytoma is diagnosed by metastasis (most often MORPHOLOGIC FEATURES Grossly, an adenoma is osseous) rather than by morphology. usually a small (2–5 cm), solitary, spherical and encapsulated The clinical features of pheochromocytoma are tumour which is well-delineated from the surrounding predominantly due to secretion of catecholamines, both ­ normal adrenal gland. Cut section is typically bright yellow. epinephrine and norepinephrine. The most common feature Microscopically, the tumour cells are arranged in trabeculae is hypertension. Other manifestations due to sudden release and generally resemble the cells of zona fasciculata. Less of catecholamines are congestive heart failure, myocardial frequently, the cells of adenoma are like those of zona infarction, pulmonary oedema, cerebral haemorrhage, glomerulosa or zona reticularis. and even death. The diagnosis is established by measuring 24-hour urinary catecholamines or their metabolites such as ­ metanephrine and VMA. Cortical Carcinoma Carcinoma of the adrenal cortex is an uncommon tumour MORPHOLOGIC FEATURES Grossly, the tumour is occurring mostly in adults. It invades locally as well as spreads soft, spherical, may be quite variable in size and weight, to distant sites. Most cortical carcinomas secrete one of the and well-demarcated from the adjacent adrenal gland. On ­ adrenocortical hormones excessively. cut section, the tumour is grey to dusky brown with areas of haemorrhages, necrosis, calcification and cystic change MORPHOLOGIC FEATURES Grossly, an adrenal (Fig. 25.3). On immersing the tumour in dichromate fixative, ­ carcinoma is generally large, spherical and well-demar it turns brown-black due to oxidation of catecholamines in ­ cated tumour. On cut section, it is predominantly yellow the tumour and hence the name chromaffin tumour. ­ with intermixed areas of haemorrhages, necrosis and Microscopically, the tumour has the following characteris- ­ calcification. tics (Fig. 25.4): Microscopically, the cortical carcinoma may vary from 1. The tumour cells are arranged characteristically as well- well-differentiated to anaplastic growth. Well-differentiated defined nests (also termed as zellballen pattern) separated carcinoma consists of foci of atypia in an adenoma, while by abundant fibrovascular stroma. tahir99 - UnitedVRG - vip.persianss.ir  791 CHAPTER 25 The Endocrine System Figure 25.4 Adrenal pheochromocytoma. The tumour has typical zellballen or nested pattern. The tumour cells are large, polyhedral and pleomorphic having abundant granular cytoplasm. Figure 25.3 Pheochromocytoma of the adrenal medulla. The specimen shows compressed kidney at the lower end (arrow) while the upper end shows a large spherical tumour separate from the kidney. Cut surface may be observed on radiologic examination of the abdomen. ­ of tumour shows cystic change while solid areas show dark brown, Metastatic spread occurs early and widely through haemato ­ necrotic and haemorrhagic tumour. genous as well as lymphatic routes and involves bones (especially skull), liver, lungs and regional lymph nodes. Neuroblastoma produces variable amounts of catecholamines ­ ­ 2. Other arrangements are as solid columns, sheets, and its metabolites such as vanillyl mandelic acid (VMA) and trabeculae or clumps. homovanillic acid (HVA), which can be detected in the 24-hour 3. The tumour cells are large, polyhedral and pleomorphic urine. Less often, the patient develops carcinoid-like syndrome, with abundant granular amphophilic or basophilic probably due to production of kinins or prostaglandins by the cytoplasm and vesicular nuclei. tumour. The features in such a case include watery diarrhoea, 4. The tumour cells of pheochromocytoma stain positively flushing of the skin and hypokalaemia. Rarely, the tumour may with neuroendocrine substances such as neuron-specific produce sufficient catecholamines to cause hypertension. enolase (NSE) and chromogranin. MORPHOLOGIC FEATURES Grossly, the tumour is Myelolipoma generally large, soft and lobulated mass with extensive areas of necrosis and haemorrhages. The tumour is usually Myelolipoma is an uncommon benign adrenal medullary diffusely infiltrating into the adjacent tissues. Cut surface tumour, sometimes found incidentally at autopsy. Less often, it of the tumour is grey white and may reveal minute foci of may produce symptoms due to excessive hormone elaboration. ­ calcification. Microscopically, neuroblastoma has the following charac MORPHOLOGIC FEATURES Grossly, a myelolipoma is ­ teristics (Fig. 25.5): usually a small tumour, measuring 0.2-2 cm in diameter. 1. The tumour cells are small, round and oval, slightly larger Microscopically, it consists of well-differentiated adipose than lymphocytes, and have scanty and poorly-defined tissue in which is scattered clumps of haematopoietic cells cytoplasm and hyperchromatic nuclei. are seen. 2. They are generally arranged in irregular sheets separated by fibrovascular stroma. Neuroblastoma 3. Classical neuroblastomas show Homer-Wright’s rosettes (pseudorosettes) which have a central fibrillar eosinophilic Neuroblastoma, also called as sympathicoblastoma, is a material surrounded by radially arranged tumour cells. common malignant tumour of neural crest cells, occurring The central fibrillar material stains positively by silver most commonly in children under 5 years of age. Vast majority impregnation methods indicating their nature as young of cases occur within the abdomen (in the adrenal medulla nerve fibrils. and paravertebral autonomic ganglia) and rarely in the 4. The tumour cells stain positively with immuno ­ cerebral hemisphere. Most cases are sporadic but 1-2% cases histochemical markers such as neuron-specific enolase are familial with autosomal dominant transmission. Familial (NSE), neurofilaments (NF) and chromogranin. ­ ­ cases are known to have germline mutation of ALK (anaplastic lymphoma kinase) gene. Prognosis of neuroblastoma depends upon a few variables; The clinical manifestations of neuroblastoma are related favourable prognostic features are as under: to its rapid local growth, metastatic spread or development i) Age of child below 2 years. of hormonal syndrome. Local symptoms include abdominal ii) Extra-abdominal location of the tumour than abdominal distension, fever, weight loss and malaise. Foci of calcification masses.