PATHOLOGY OF ENDOCRINE SYSTEM

Department of Pathology GMUSM

Hypophysis
A. Anterior pituitary (adenohyphophysis) 1. Anterior pituitary hyperfunction a. Prolactinoma with hyperprolactinemia - is most common/30% pituitary tumor - staining chromophobe - in women amenorrhea & galactorrhea - caused by hypothalamic lesions or mediations methyl dopa, reserpine interfere with dopamine (prolactin-inhibitory factors) secretion - can also be associated with estrogen therapy

b. Somatotropic adenoma with hypersecretion of growth hormone - 2nd most common pituitary tumor - staining acidophyl - causes secondary hyperfunction of somatomedins by the liver. End organ effects are caused by both growth hormone and somatomedins, especially somatomedin C (insulin-like growth factor 1/IGF-1) - results gigantism if adenoma develops before epiphyseal closure and acromegaly if adenoma develops after epiphyseal closure - acromegaly overgrowth of jaws, face, hands and feet, and general enlargement of viscera with hyperglycemia, osteoporosis and hypertension - can also result in local compression effects due to expansion of the tumor within the sella tursica

 Corticotropic adenoma and hypersecretion of ACTH - results in increased production of ACTH / hypercorticism - is called Cushing syndrome or Cushing disease 1. Cushing disease hypercorticism adenoma most often a basophilic adenoma basophilic microadenoma 2. Cushing syndrome hypercorticism regardless of cause, is most often of pituitary and less often of adrenal origin may be due to ectopic ACTH production by various tumors especially small cell carcinoma of lung

Anterior pituitary hypofunction

a. Pituitary cachexia (Simmonds disease) - is generelized panhypopituitarism - characterized by marked wasting - can result from any process that destroy the pituitary Etiology: (1) Pituitary tumors (2) Post partum pituitary necrosis (Sheehan syndrome) - is caused by ischemic necrosis of pituitary gland, characteristically associated with hemorrhage and shock during childbirth - clinical manifestations are due at first to loss of gonadotropins, then to subsequent loss of TSH and ACTH

b. Selective deficiency of one or more pituitary hormones (1) deficiency of growth hormone - in children, result in growth retardation (pituitary dwarfism) - in adults, may result in increased insulin sensitivity with hypocalcemia, decreased muscle strength and anemia (2) deficiency of gonadotropins - in preadolescent children, results in retarded sexual maturation - in adults, results in loss of libido, impotence, loss of muscular mass, and decreased hair in men, and amenorrhea and vaginal atrophy in women (3) deficiency of TSH - result in secondary hypothyroidism (4) deficiency of ACTH - results in secondary adrenal failure - does not result in hyperpigmentation of the skin, probably because of lack of both ACTH and -MSH; this is in contrast to primary adrenal failure (Addison disease), in which ACTH is increased and hyperpigmentation is the rule

Growth hormone containing cell in adenoma of adenohyphophysis Immunoperoxidase staining method

POSTERIOR HYPOPHYSIS (NEUROHYPOPHYSIS)

HORMONES - are synthesized in the hypothalamus and transported via axons to the posterior pituitary a. Oxytocin : induces uterine contarction during labor and ejection of milk from mammary alveoli b. Anti diuretic hormone (ADH, vasopressin) - promotes water retention through action on the renal collecting ducts

 Syndrome of inappropriate ADH(SIADH) secretion is most commonly caused by ectopic production of ADH by various tumors, especially small cell carcinoma of lung. Results in retention of water with consequent dilutional hyponatremia, reduced serum osmolality, and inability to dilute urine Deficiency of ADH: results in diabetes insipidus; characterized by polyuria, with consequent dehydration and insatiable thirst - can be caused by tumors, trauma, inflammatory processes, lipid storage disorders, and other conditions characterized by damage of the neurohypophysis or hypothalamus

C. NON FUNCTIONING PITUITARY TUMORS

Non secreting pituitary adenomas - are most often chromophobe - result in dysfunction because of local pressure phenomena - are clinically variable ;manifestations include hypopituitarism, headache,visual disturbance (bilateral hemianopsia / loss of peripheral visual fields due to pressure on optic chiasm), and palsies caused by cranial nerve damage

 Craniopharyngioma
- is benign childhood tumor derived from remnants of the Rathke pouch - is not a true pituitary tumors - similar to ameloblastoma of the jaw - is characterized by nests and cords of squamous or columnar cells in loose stroma, closely resembling the appearance of the embryonic tooth bud enamel organ - is often cystic; lining epithelium of flat or columnar cells often expands into papillary projections - is often detected radiographically because of calcification

Craniopharyngioma : masses of keratin within tumour masses composed of loosely packed stellate epithelial cells surrounded by a pallisaded basal layer bordering an oedematous stroma

PATHOLOGY OF THYROID AND PARATHYROID GLAND

Harijadi Department of Pathology GMU SM

NORMAL THYROID GLAND

Autoimmune disease of thyroid gland

HYPERTHYROIDISM
GRAVES THYROIDITIS
FUNCTIONAL ADENOMA TOXIC NODULAR GOITRE

GRAVES DISEASE

Gross specimen of Graves disease

MICROSCOPIC SPECIMEN OF GRAVES disease

Hypothyroidism
Syndrome due to insufficient circulating T3 and T4 If congenital cause cretinism Commonest case are Hashimotos thyroiditis, an autoimmune disease and endemic goitre

Papillary carcinoma thyroid

Follicular carcinoma of thyroid

Anaplastic carcinoma of thyroid

Medullary carcinoma of thyroid

PARATHYROID GLAND

Parathyroid adenoma

Parathyroid adenoma

Pathology of adrenal glands

Harijadi Department of Pathology GMUSM

Normal adrenal gland

NORMAL CORTEX ADRENAL

Adrenal glands
CORTEX - Hypercorticism / Cushing syndrome - Hyperaldosteronism - Adrenal virilsm - Hypocorticism MEDULLA - Pheochromocytoma - Medulloblastoma

ADRENOCORTICAL HYPERPLASIA The adrenal cortex are yellow, thickened and multinodular

ADRENOCORTICAL ADENOMA SOLITARY, CIRCUMSCRIBED

ADRENAL CORTICAL ADENOMA

Cells in adrenocortical adenoma

Compact adenoma

Black cortex adenoma in Cushing syndrome

Morphologic changes in adrenal glands

Bilateral hyperplasia of adrenal zona fasciculata occurs when the syndrome results from ACTH stimulation Adrenal cortical atrophy is seen when exogenous glucocorticoid medication is cause Adrenal cortical adenoma or carcinoma - Adenoma is more common - cannot be supressed by exogenous adrenal steroids in dexamethasone supression test, in contrast, hypercorticism of pituitary origin can usually be supressed useful diagnosis measures in determining the cause of hypercorticism. - ACTH increased in pituitary hypercorticism and in ectopic ACTH production, and it is low when hypercorticism is adrenal origin

Clinical characteristics of hypercorticism

Redistribution of body fat with round moon face, dorsal buffalo hump, often with relatively thin extremities caused by muscle wasting; skin atrophy with easy bruishing and purplish striae, especially over abdomen , and hirsutism Muscle weakness, osteoporosis, amenorrhea, hypertension, hyperglycemia, and psychiatric dysfunction

HYPERALDOSTERONISM
Primary aldosteronism ( Conn syndrome) - is caused by primary hyperfunction od adrenal mineralocorticoids - usually results from an aldosteron-producing adrenocortical adenoma (aldosteronoma) - can results from hyperplasia of the zona glomerulosa - may rarely caused by adrenocortical carcinoma - is characterized clinically by hypertension, sodium and water retention, and hypokalemia, often with hypokalemic alkalosis - demostrates decreased serum renin due to negative feedback of increased blood pressure on renin secretion

 Secondary aldosteronism - is secondary to renal ischemia, renal tumors, and edema( e.g. cirrhosis, nephrotic syndrome, cardiac failure) - is caused by stimulation of the renin-angiotensin system - demonstates increased serum renin. In contrast to primary aldosteronism. Renin synthesized in the juxta glomerular apparatus of the kidney promotes the conversion of angiotensigen to angiotensin I, which converted catalytically by angiotensin converting enzyme (mainly in lung) to AT II. The release of aldosterone is facilitated by AT II.

Adrenal virilism (adrenogenital syndrome)

Causes a. Congenital enzyme defect result in deminished corticol production and compensatory increased ACTH, with resultant adrenal hyperplasia with androgenic steroid production (1) 21- hydroxylase deficiency most common result in salt loss and hypotension (2) 11- hydroxylase deficiency less common results in salt retention and hypertension b. Tumor of the adrenal cortex Clinical characteristic: - produces virilism in females and precocious puberty in males

HYPOCORTICISM (adrenal hypofunction)

Can be primary adrenal cause or secondary to hypothalamic or pituitary hypofunction Is characterized by deficiency of glucocorticoid (primary cortisol) , often associated with mineralocorticoid deficiency
1. ADDISON DISEASE 2. Waterhouse Friderichsen syndrome

ADDISON DISEASE
Is most commonly due to idiopathic adrenal atrophy ( autoimmune lymphocytic adrenalitis) Can also be caused by tuberculosis, metastatic tumors and various infections.
Is characterized by hypotension; increased pigmentation of skin; decreased serum sodium, chloride, glucose, and bicarbonate; and increase of serum potasium

Waterhouse Friderichsen syndrome

Is catastrophic adrenal insufficiency and vascular collapse due to hemorrhagic necrosis of the adrenal cortex Is often associated with disseminated intravascular coagulation Is characteristically due to meningococcemia, most often in association with meningococcal

Adrenals in WaterhouseFriderichsen syndromedestroyed by hemorrhage

Tumors of adrenal medulla

1. Pheochromocytoma
Is derived from chromaffin cells of adrenal medulla ( if derived from extra-adrenal chromaffin
cells, called paraganglioma

Most often benign, only 10% malignant Is characterized by increased urinary excretion of catecholamines (epinephrine or norepinephrine) and their metabolites ( metanephrine, normetanephrine, and vanillymandelic acid (VMA) Can also cause hyperglycemia Can be part of MEN IIa or MEN IIb(III) Can also be associated with bneurofibromatosis or with von Hippel-Lindau disease

Pheochromocytoma

the adrenal medulla is expanded by a darked-coloured tumour with areas of degeneration and hemorrhage

Pheochromocytoma
left adrenal

right normal

Chromaffin cells in pheochromocytoma

2. Neuroblastoma
Is highly malignant catecholamine producing tumor in early childhood. Urinary catecholamine and cathecolamine metabolites are the same as in pheochromocytoma Causes hypertension Usually originates in the adrenal medulla and often presents as a large abdominal mass Occasionally converts into a more differentiated form termed ganglioneuroma Is characterized by amplification of the N-myc oncogene with thousands of gene copies per cell a. Amplification results in karyotypic changes homogenous staining regions or double minutes chromosomes b. the number of N-myc gene copies is related to the aggressiveness of the tumor c. the malignant neuroblastoma sometimes differentiate into benign cells, and this changes is reflected by a marked reduction of gene amplification

Microscopic appearance of neuroblastoma neurogenic primitive cells

MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES

Are a group of autosomal dominant syndromes in which more than one endocrine organ are hyperfunctional May be associated with hyperplasia or tumors MEN I ( Werner syndrome) MEN IIa (Sipple syndrome) MEN IIb / III

MEN I (WERMER SYNDROME)

Includes hyperplasia or tumors of the pituitary, parathyroid, or pancreatic islets (3Ps) Additionally may include hyperplasia or tumors of the thyroid or adrenal cortex May manifest its pancreatic component by the Zollinger-Ellison syndrome, hyperinsulinism, or pancreatic cholera Is linked to mutations in the MEN I gene

 MEN IIa (Sipple syndrome) - includes pheochromocytoma, medullary carcinoma of thyroid, and hyperparathyroidism due to hyperplasia or tumor - is linked to mutations in the ret oncogene MEN IIb / III - Includes pheochromocytoma, medullary carcinoma, and multiple mucocutaneous neuroma or ganglioneuroma. In contrast to MEN IIa, does not induce hyperparathyroidism. - is linked to different mutations in the ret oncogene than is MEN IIa

NORMAL PANCREAS

Staining of immunoperoxidase technique for insulin insulin containing cells are darkly stained

TYPES OF DM

TYPE I VERSUS TYPE II DM

DIABETES MELLITUS
Classification and general features A. Type 1 (insulin-dependent diabetes mellitus / IDDM), juvenile or ketosis-prone diabetes mellitus - often begins early in life, before age 30 - is less common than type 2 - is due to failure insulin synthesis by beta cells of the pancreas islets - a genetic predisposition complicated by autoimmune inflammation / insulinitis triggered by a viral infection or environmental factors. Family history less frequently than type 2 DM - Increased incidence with specific point mutation of HLA- DQ gene, and incidence markedly increased in HLA-DR3- and HLA-DR4-positive individuals - marked carbohydrate intolerance with hyperglycemia, leading polyuria, polydipsia, weight loss despite increased appetite, ketoacidosis, coma and death - ketoacidosis keton bodies increased catabolism of fat

 B. Type 2 (non-insulin dependent diabetes mellitus / NIDDM, adult onset, ketosisresistent DM - More common than type 1 DM - Most often in middle age - due to increased insulin resistance mediated by decreased cell membrane insulin receptors or post receptor dysfunction, impaired processing of proinsulin to insulin, decreased sensing of glucose by beta cells, or impaired function of intracellular carrier proteins

(1) Etiologic factors (a) positive family history more frequent than type 1 (b) most often associated with mild to moderate obesity (2) Characteristics (a) normal, often increased, plasma insulin concentration (b) mild carbohydrate intolerance, most often managed by oral antidiabetic agents; insulin therapy is not usually required (c) ketoacidosis is unsual but does occur, characteristically precipitated by unusual stress such as infection or surgery

C. Maturity-onset diabetes mellitus of the young (MODY) - an autosomal dominant syndrome characterized by mild hyperglycemia and hyposecretion of insulin, but without loss of beta cells - onset earlier than type 2 DM - is caused by a diverse group of single gene defects D. Secondary DM occurs as a secondary phenomenon in pancreatic and other endocrine disease and pregnancy (a) pancreatic disease - hereditary hemochromatosis (bronze diabetes) excess iron absorption and parenchymal deposition of hemosiderin, with reactive fibrosis in various organs, especially pancreas, liver and heart (b) pancreatitis acute pancreatitis hyperglycemia, chronic pancreatitis islet cell destruction and secondary DM (c) carcinoma of pancreas DM may be the presenting sign

Other endocrine diseases

Cushing syndrome produces hyperglycemia a s a result of increased gluconeogenesis and impaired peripheral utilization of glucose Acromegaly produces hyperglycemia due to the anti- insulin like effect of GH Glucagon hypersecretion promotes glycogenolysis is characteristically caused by an islet alpha cell tumor (glucagonoma) Phaeochromocytoma and hyperthyroidism are sometimes associated with hyperglycemia

Pregnancy
May associated with transient DM (gestational diabetes) Is characteristically associated with increased fetal birth weight and increased fetal mortality, notably from neonatal respiratory distress syndrome (hyaline membrane disease) When the mother has hyperglycemia can result in an infant born with hyperplasia of the pancreatic islets and hypoglycemia

Pathologic changes in DM
Pancreas islets (1) Type 1 DM islets are small and beta cells are greatly decreased in number or absent; insulinitis marked by lymphocytic infiltration is highly specific early change (2) Type 2 DM focal islet fibrosis and hyalinization due to deposit amylin are characteristic but not specific. Amylin (islet amyloid polypeptide/IAPP) deposition in pancreatic islet is characteristic of type 2 DM and thought to interfere either with conversion of proinsulin to insulin or with the sensing of insulin by beta cells

Amyloid of a pancreatic islet

Hyaline arteriolosclerosis of afferent arteriole of kidney

Nodular glomerulosclerosis

Nephrosclerosis in long standing diabetes

Diabetic retinopathy

ISLET CELL TUMOR

Insulinoma (beta cell tumor) - is most common islet cell tumor - benign / malignant - characterized by greatly increased of insulin - clinically Whipple triad 1. episodic hyperinsulinemia and hypoglycemia 2. CNS dysfunction temporally related to hypoglycemia (confusion, anxiety, stupor, convulsion, coma) 3. Dramatic reversal of CNS abnormalities by glucose administration

Insulinoma : ribbon or brown stained cells resembling those of the normal islet of Langerhans

 Gastrinoma - is often a malignant tumor, sometimes occuring in extrapancreatic sites - results in gastrin hypersecretion and hypergastrinemia - is associated with Zollinger-Ellison syndrome ( marked gastric hypersecretion of HCl, recurrent peptic ulcer disease and hypergastrinemia