PATHOLOGY OF THE ADRENAL GLANDS-CORTEX AND MEDULLA, | ts/10/2021 MEN SYNDROMEINTRODUCTION The adrenal glands, also called the suprarenal glands, are a significant part of the endocrine system. The paired adrenal glands are triangular-shaped organs that measure approximately 5 cm by 2 cm, are located on the superior aspect of ach kidney, and weigh 4 to 5 grams each. The adrenal glands secrete several vital hormones that play a significant role in the regulation of the immune system, body metabolism, salt, and water balance, and aid the body during periods of stress.The adrenal gland is composed of two distinct regions > Adrerial cortex- derived from mesoderm » Adrenal medulla. derived from neural crest cells. It is composed of chromafin cells which synthesizes catecholamines. Constitutes 15% of the adrenal gland The adrenal cortex is also divided into 3 zones ‘ona glomerulosa “Zona fasciculata “Zona reticularis The names of these zones can also be recalled by remembering "GFR" for Glomerulosa, Fasciculata, and ReticularisZona glomerulosa (outer layer) The zona glomerulosa is responsible for the synthesis of mineralocorticoids, of which the most important is aldosterone. This hormone plays an important role in electrolyte balance and regulation of blood pressure. Pathology: conn syndrome manifested by hyperaldosteronismZona fasciculata (middle layer) The zona fasciculata produces glucocorticoids, of which the predominant hormone is cortisol. This hormone plays a role in the regulation of blood sugar via gluconeogenesis. Cortisol also modulates the immune system and modulates the metabolism of fat, protein, and carbohydrates. The secretion of cortisol is under the regulation of adrenocorticotropic hormone, which is released from the pituitary gland. Pathology- cushing’s disease- manifests as elevated levels of cortisolZona reticularis (inner zone) The zona reticularis produces androgens and plays a role in the development of secondary sexual characteristics. The primary androgen produced in the zona reticularis is dehydroepiandrosterone (DHEA), which is the most abundant hormone in the body. It serves as a precursor for the synthesis of many other hormones produced by the adrenal gland, such as progesterone, estrogen, cortisol, and testosterone. Pathology- precocious puberty.ADRENOCORTICAL HYPERFUNCTION: HYPERADRENALISMThere are three distinctive hyperadrenal clinical syndromes, each caused by abnormal production of one or more of the hormones produced by the three layers of the cortex: “Cushing syndrome, characterized by an excess of cortisol “*Hyperaldosteronism, caused by an excess of mineralocorticoid “Adrenogenital or virilizing syndromes, caused by an excess of androgensHYPERCORTISOLISM: CUSHING SYNDROME Hypercortisolism (Cushing syndrome) is caused by elevated glucocorticoid levels. Causes “Exogenous glucocorticoids-commonest cause “Hypothalamic-pituitary disease- cushing disease. 70% of endogenous causes.4x more common in women (20s-30s)- pituitary adenoma, corticotroph cell hyperplasia, hypothalamus CRH releasing tumor- leads to bilateral nodular cortical hyperplasia- hypercortisolism* Secretion of ectopic ACTH by non pituitary neoplasms- 10%- scc lung,MTC,NETs. Occasionally neuroendocrine neoplasms produce ectopic CRH, which, in turn, causes ACTH secretion. These conditions also lead to bilateral cortical hyperplasia and lead to hypercortisolism. Primary adrenocortical neoplasms- adenoma/carcinoma, cortical hyperplasia 15-20%. They are also called ACTH-independent cushing syndrome. The biochemical hallmark of adrenal Cushing syndrome is elevated levels of cortisol and low serum levels of ACTH.Morphologic changes in the adrenal glands also depend on the cause of the hypercortisolism and include: “cortical atrophy “diffuse hyperplasia “macronodular or micronodular hyperplasia “san adenoma or carcinoma,In patients in whom the syndrome results from exogenous glucocorticoids, suppression of endogenous ACTH results in bilateral cortical atrophy, due to a lack of stimulation of the zona fasciculata and zona reticularis by ACTH. The zona glomerulosa is of normal thickness in such cases, because this portion of the cortex functions independently of ACTH. In cases of endogenous hypercortisolism, by contrast, the adrenals either are hyperplastic or contain a cortical neoplasm.Diffuse hyperplasia is found in patients with ACTH dependent Cushing syndrome. Both glands are enlarged, either subtly or markedly, each weighing up to 30 g. The adrenal cortex is diffusely thickened and variably nodular. The yellow color of diffusely hyperplastic glands derives from the presence of lipid-rich cells, which appear vacuolated under the microscope. In primary cortical hyperplasia, the cortex is replaced almost entirely by macronodules or 1- to 3-mm micronodulesCLINICAL FEATURES Hypertension Weight gain- characteristic centripetal redistribution of adipose tissue with truncal obesity, moon facies and accumulation of fat in the posterior neck and back (buffalo hump) Glucocorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells, resulting in secondary diabetes Hyperglycemia Glucosuria Polydipsia Hypercortisolism causes selective atrophy of myofibers, with resultant decreased muscle mass and proximal limb weaknessIncreased woes Weight gain Purple striae Pendulous abdomen is resulting from easy bruising‘The catabolic effects of insulin resistance on proteins cause loss of collagen. Thus, the skin is thin, fragile, and easily bruised; cutaneous striae are particularly ‘common in the abdominal area. Cortisol also causes bone resorption leading to osteoporosis. — susceptibility to fractures. Glucocorticoids suppress the immune response- increased infections psychiatric symptoms -mood swings, depression,and frank psychosis Hirsutism Menstrual abnormalities Hyperpigmentation of skin- in extradrenal cushings due to melanocyte stimulating activity in the ACTH precursor molecule.HYPERALDOSTERONISM Conditions characterized by chronic excess aldosterone secretion. Can be primary or secondary(extraadrenal cause) Primary hyperaldosteronism It refers to autonomous overproduction of aldosterone with resultant suppression of the renin-angiotensin system and decreased plasma renin activity.Causes “Bilateral idiopathic hyperaldosteronism characterized by bilateral nodular hyperplasia of adrenal glands. Commonest cause 60% of cases, cause unclear. “Adrenocortical neoplasm- aldosterone producing adenoma (conn syndrome) or adrenocortical carcinoma “Familial hyperaldosteronism-genetic defect that leads to overactivity of the aldosterone synthase gene, CYP11B2.Secondary hyperaldosteronism Aldosterone release occurs in response to activation of the renin- angiotensin system. This condition is characterized by increased level of plasma renin. Causes Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis) “Arterial hypovolemia and edema (congestive heart f nephrotic syndrome) re, cirrhosis, “Pregnancy (caused by estrogen-induced increases in plasma renin substrate)CLINICAL FEATURES Hypertension- most common cause of secondary HTN- The long-term effects are cardiovascular compromise (e.g., left ventricular hypertrophy and reduced diastolic volumes) and an increase in the prevalence of adverse events such as stroke and myocardial infarction. Hypokalemia- weakness, paresthesias, visual disturbances, and occasionally frank tetany.Treatment Surgery for adenomas Aldosterone antagonist e.g. spironolactone in bilateral hyperplasia For secondary hyperaldosteronism- treat the underlying cause.ADRENOGENITAL SYNDROMES Refers to a group of disorders caused by androgen excess. The adrenal cortex secretes two compounds— dehydroepiandrosterone and androstenedione—which require conversion to testosterone in peripheral tissues for their androgenic effects. Adrenal androgen formation is regulated by ACTHCauses “Cushings disease Adrenocortical neoplasm. likely to be carcinoma “CAH- congenital adrenal hyperplasia- AR disorders characterized by a hereditary defect in an enzyme involved in adrenal steroid biosynthesis, particularly cortisol. Decreased cortisol leads to a compensatory increase in ACTH. This results in adrenal hyperplasia with increased production of cortisol precursor steroids, which are then channeled into synthesis of androgens with virilizing activity.Certain enzyme defects also may impair aldosterone secretion, adding salt loss to the virilizing syndrome. The most common enzymatic defect in CAH is 21-hydroxylase deficiency, which accounts for more than 90% of cases. 21-hydroxylase is required for synthesis of cortisol and aldosterone but not sex steroids. Thus, a deficiency of this enzyme reduces cortisol and aldosterone synthesis and shunts the common precursors into the sex steroid pathway.CLINICAL FEATURES b The clinical manifestations of CAH are determined by the specific enzyme deficiency. In 21-hydroxylase deficiency > Masculinization in females- clitoral hypertrophy, pseudohermaphroditism in infants. Oligomenorrhea, Hirsutism, Acne » In males- enlargement of external genitalia, oligospermia » Salt wasting CAH should be suspected in any neonate with ambigous genitalia RX. Exogenous glucocorticoids and Mineralocorticoid supplementation in the salt-wasting variants of CAH.ADRENAL INSUFFICIENCY |Adrenocortical insufficiency, or hypofunction, may be caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the adrenals resulting from ACTH deficiency (secondary hypoadrenalism). Primary adrenocortical insufficiency may be acute (called adrenal crisis), or chronic (Addison| ACUTE ADRENOCORTICAL INSUFFICIENCY Causes “Individuals with chronic adrenocortical insufficiency may develop an acute crisis after any stress that taxes their limited physiologic reserves. “Sudden withdrawal of longterm corticosteroid therapy- adrenal atrophy “Massive adrenal hemorrhage- anticoagulant therapy, DIC, waterhouse-friderichsen syndrome (overwhelming sepsis in N.meningitidis)CHRONIC ADRENOCORTICAL INSUFFICIENCY: ADDISON DISEASE Results from progressive destruction of the adrenal cortex Causes “Autoimmune adrenalitis- 60-70% of cases where infections are uncommon.- autoantibodies to steroidogenic enzymes- adrenals appear shrunken, “TB- the adrenal architecture is effaced by granulomatous inflammation “AIDS “Fungi- H.capsulatum, coccidiodes immitis “Viral infections- CMV “Metastatic cancer lung and breast- adrenals are enlarged and architecture obscured by the infiltrating tumorSECONDARY ADRENOCORTICAL INSUFFICIENCY Results from any disorder of the hypothalamus and pituitary that reduces the output of ACTH. Causes “Infections “Infarction “slrradiation Metastatic tumor ACTH deficiency may occur alone or as part of panhypopituitarism. It is characterized by deficient cortisol and androgen output but normal or near-normal aldosterone synthesis It is characterized by low serum ACTH and a prompt rise in plasma cortisol levels in response to ACTH administration.ht CLINICAL FEATURES Present when atleast 90% of the adrenal cortex is compromised. » Progressive weakness > Easy fatigability » GIT- anorexia, N,V, D > Weight loss > Hyperpigmentation of skin in primary causes- face, axillae, nipples, areolae, perineum hypoglycemia » aldosterone def- hyponatremia, hyperkalemia, volume depletion, hypotension Adrenal crisis- intractable vomiting, abdominal pain, hypotension, coma, vascular collapse and eventually death.ADRENOCORTICAL NEOPLASMS Can be adenomas or carcinomas Functional vs non-functional. Most adenomas are non functional and are encountered as incidental findings (adrenal incidentaloma). Small 1-2cm in diameter and composed of cells similar to those populating the normal adrenal cortex Functional adenomas usually result in hyperadrenalism Carcinomas- virilizing neoplasm. Are rare. Can occur in Li-fraumeni syndrome, Beckwith-Wiedemann syndrome. Are large and efface the adrenals. Have areas of necrosis, hemorrhage and cystic changes. Can Invade adrenal vein, IVC, lymphatics. Mets to lungs, bone, other viscera. carcinomas metastatic to the adrenal cortex are significantly more frequent than a primary adrenocortical carcinomaPHEOCHROMOCYTOMA Neoplasm of chromaffin cells that synthesize and release catecholamines and other peptide hormones. They cause hypertension Pheochromocytomas usually subscribe to a convenient “rule of 10s”: 10% are extraadrenal- which occur in the organ of Zuckerkandl and the carotid body, where they usually are called paragangliomas, rather than pheochromocytoma10% are bilateral- 50% ass with familial syndromes “10% are malignant * 10% not associated with hypertension.25% harbor germ line mutations in one of atleast 6 genes RET, NF1, VHL, succinate dehydrogenase complex genes( SDHB, SDHC, SDHD). Pheochromocytoma range from small circumscribed lesions to large hemorrhagic masses. Both capsular and vascular invasion, as well as cellular pleomorphism, may be encountered in some benign lesions. Therefore, the definitive diagnosis of malignancy in pheochromocytomas is based on the presence of metastases.CLINICAL FEATURES Hypertension-2/3 have paroxysmal episodes ass with an abrupt, precipitous elevation in blood pressure, associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension. Sudden elevations in BP may precipitate CHF, pulmonary edema, Ml, ventricular fibrillation and CVA Abdominal pain, N,V In some cases pheochromocytomas secrete other hormones such as ACTH and somatostatin and may therefore be associated with clinical features related to the effects of these and other peptide hormones.The laboratory diagnosis is based on demonstration of increased urinary excretion of free catecholamines and their metabolites, such as vanillylmandelic acid and metanephrines. Isolated benign pheochromocytomas are treated with surgical excision. With multifocal lesions, long-term medical treatment for hypertension may be required.NEUROBLASTOMA 4th most common malignant tumor in childhood Median age at presentation 23 months, peak 0-4 years Slightly more common in boys Occurs anywhere in distribution of sympathoadrenal neuroendocrine system. Most in adrenal gland (~40%), followed by connective / subcutaneous / soft tissue (~20%), retroperitoneum (~15%), mediastinum (~10%). Results from clonal proliferation of immature cells of neural crest originCLINICAL FEATURES Clinical features depend on location / extent of tumor Severe ill health, malnourishment, pain all suggest metastatic disease Abdominal mass Watery diarrhea syndrome (6%) Opsoclonus-myoclonus-ataxia syndrome: rapid eye movements, ataxia, irregular muscle movements Heterochromia iridis: cervical, mediastinal neuroblastoma (prenatal / postnatal interruption of sympathetic tracts that mediate pigmentation of iris) Horner's syndrome (damage to sympathetic trunk resulting In mlosls, ptosls, enophthalmos, anhidrosis): head, neck, thorax tumors Paralysis: paraspinal tumors Skin bruising associated with metastases to skin Raccoon eyes associated with metastases to orbit cause bruising and proptosisMULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMESThese are a group of inherited diseases caused by proliferative lesions (hyperplasias, adenomas, and carcinomas) of multiple endocrine organs Characteristics occur at a younger age » Arise in multiple endocrine organs, either synchronously (at the same time) or metachronously (at different times). » Even in one organ, the tumors often are multifocal. » The tumors usually are preceded by an asymptomatic stage of endocrine hyperplasia invelving the cell of origin of the tumor » The tumors are usually more aggressive and recur in a higher proportionMEN TYPE 1 It is caused by germ line mutations in the MENT tumor suppressor gene, which encodes a protein called Menin. Inherited as AD. Organs most commonly involved are the parathyroid, the pancreas, and the pituitary—the “3 Ps.” Parathyroid- Primary hyperparathyroidism is the most common manifestation of MEN-1 (80%-95% of patients) and is the initial manifestation of the disorder in most patients, appearing in almost all by 40 to 50 years of age. Parathyroid abnormalities include hyperplasia and adenomas.Pancreas- Endocrine tumors of the pancreas are the leading cause of death in MEN-1. These tumors usually are aggressive and present with metastatic disease. Pancreatic endocrine tumors often are functional (i.e., secrete hormones). Zollinger-Ellison syndrome, associated with gastrinomas, and hypoglycemia, associated with insulinomas, are common endocrine manifestations. Pituitary. The most frequent pituitary tumor in patients with MEN-1 syndrome is a prolactin-secreting macroadenoma. In some cases, acromegaly develops in association with somatotropin-secreting tumors.MEN TYPE 2 Inherited in an AD pattern It comprises two distinct groups of disorders that are unified by the occurrence of activating (i.e., gain-of-function) mutations of the RET proto-oncogene at chromosomal locus 10q11.2. Differences in mutation patterns account for the variable features in the two subtypes.MEN TYPE 2A ‘Organs include Thyroid- Medullary carcinoma of the thyroid develops in virtually all untreated cases, and the tumors usually occur in the first 2 decades of life. The tumors commonly are multifocal, and foci of C cell hyperplasia can be found in the adjacent thyroid. Familial medullary thyroid cancer is seen in a variant of MEN-2A, without the other characteristic manifestations . In comparison with MEN-2, familial medullary carcinoma typically occurs at an older age and follows a more indolent course.Adrenal medulla: Adrenal pheochromocytomas develop in 50% of the patients; fortunately, no more than 10% of these tumors are malignant. Parathyroid: Approximately 10% to 20% of patients develop parathyroid gland hyperplasia with manifestations of primary hyperparathyroidismMEN TYPE 2B It results from a single amino acid change in RET gene. Organs affected Thyroid- Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A. Adrenal medulla- pheochromocytoma There is no parathyroid involvement This patients also have extraendocrine manifestations which include ganglioneuromas of mucosal sites (gastrointestinal tract, lips, tongue) and a marfanoid habitus, in which overly long bones of the axial skeleton give an appearance resembling that in Marfan syndrome fsMEN 1 Pituitary adenoma Parathyroid hyperplasia Parathyroid hyperplasia Medullary thyroid carcinoma MEN 2B Mucosal neuromas Marfanoid body habitus Medullary thyroid carcinoma Pheo- chromo- cytoma