Endocrine Pathology | Adrenal Gland | Thyroid

Pathology (dr.

Yabut) Endocrine Patholgy 09 January 08

PITUITARY GLAND
-A pea-sized gland, weighs 0.5 gm & measures 1cm,

attached to the hypothalamus by a stalk -Two lobes: anteroir & posterior -Anterior lobe (adenohypophysis)

-derived from Rathke’s pouch -contains cells that secrete trophic hormones
that activate peripheral endocrine glands

-hypothalamic releasing hormones are delivered
via a portal venous system Posterior lobe (neurohypophysis) derived from outpouching from floor of 3rd ventricle has a separate blood supply consists of modified glial cells & axons extending from the supraoptic & paraventricular nuclei in the hypothalamus - neurons in the supraoptic & paraventricular nuclei produce ADH & oxytocin - ADH & oxytocin are stored in axon terminals in the post. Lobe

THE ADENOHYPOPHYSIS - Five cell types in the adenohypophysis by immunostaining: 1- Lactotrophs (Mammotrophs): Prolactin (Prl) acidophils. 2- Somatotrophs: growth hormone (GH) acidophils. 3- Corticotrophs: proopiomelanocortin (POMC) precursor for adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), β-endorphin, and β-lipotropin - basophils. 4- Thyrotrophs: thyroid stimulating hormone (TSH) - basophils. 5- Gonadotrophs: follicle stimulating hormone (FSH) & luteinizing hormone (LH) - basophils. Hypothalamic Releasing Hormone Gonadotropin Releasing Hormone (GnRH) * Growth Hormone Releasing Hormone (GRH) * Corticotropin Releasing Hormone (CRH) * Thyrotropin Releasing Hormone (TRH) * Dopamine ** * stimulatory ** inhibitory DISEASES OF THE ADENOHYPOPHYSIS -⇑ function: Hyperpituitarism -⇓ function: Hypopituitarism Corresponding Anterior Pituitary Hormone(s) Luteinizing Hormone (LH) Follicular Stimulating Hormone (FSH) Growth Hormone (GH) Adrenocorticotropic Hormone (ACTH) Thyroid Stimulating Hormone (TSH) Prolactin (PRL)

-nonfunctional adenoma -inflammatory lesions -ischemic injury
-mass effects

-enlargement of sella turcica -visual field defects (classically bitemporal
hemianopsia)

-⇑ intracranial pressure -headache, blurring of vision -nausea and vomiting
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CAUSES OF HYPERPITUITARISM
1 2 3 4 - Primary hypothalamic disorders (rare) - Primary Pituitary Hyperplasia (rare) - Functioning carcinomas (extremely rare) - Functioning Adenomas (MCC). Classified as: 1. Prolactinomas (Prl) 2. Somatotroph (GH) adenomas 3. Corticotroph (ACTH) adenomas 4. Gonadotroph (FSH/LH) adenomas 5. Thyrotroph (TSH) adenomas 6. Pleurihormonal adenomas (GH+Prl). Monoclonal but polyhormonal, or mixed-cell adenomas.

HYPERPROLACTINEMIA (amenorrheagalactorrhea syndrome) The MC pituitary hyperfunction syndrome. Caused by: 1- Prolactinomas;

-Prl secreting adenoma (sparsely granulated,
chromophobic)

-F/M >1, peak incidence 20-30 yrs. of age -serum prolactin level > 300 ug/L is diagnostic -Rx: surgery (transsphenoidal)
bromocriptine (dopamine receptor agonist) radiation 2- Hypothalamic diseases. Hypothalamus normally produces dopamine (Prl-inhibitory factor).

-head trauma, etc. -stalk effect
3- Anti-dopaminergic drugs (phenothiazines, haloperidol) 4- Estrogen therapy 5- Primary Hypothyroidism (⇑ TRH ⇒ ⇑ Prl) Signs & Symptoms: - women: galactorrhea, amenorrhea, infertility, ⇓ libido

-

men: ⇓ libido, impotence & rarely galactorrhea & gynecomastia

SOMATOTROPH ADENOMAS Acromegaly; -adult onset excess growth hormone (GH) ⇒ enlargement of the skull, facial bones, jaw, hands, feet, soft tissues & organs. -diabetes, hypertension, muscle weakness, arthritis, gonadal dysfunction, cardiovascular disease Gigantism; -GH excess occurs in children (before closure of epiphyses). -generalized increase in body size -disproportionately long arms and legs

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* Morphology: macroadenomas, composed of densely or sparsely granulated “acidophilic” cells, strongly positive for GH by immunostains. - 30% elaborate both GH and Prl (a mixed cell adenoma or a single cell-type pleurihormonal adenoma). 40% express the gsp oncogene GH acts indirectly by ⇑ hepatic secretion of insulin-like growth factor-1 (IGF-1) Diagnosis: ⇑ serum GH & IGF-1 serum prolactin may be elevated glucose suppression test imaging scans (MRI better than CAT scan) Treatment: transsphenoidal surgery, octreotide acetate, radiation

Pathologic Entity

ACTH Secreting Pituitary Adenoma Cortisol Secreting – Adrenocortical Neoplasm ACTH Secreting – Nonendocrine Neoplasm

Low High Dose Dose – + –

OTHER FUNCTIONING ADENOMAS Gonadotroph adenomas:

-majority produce FSH, some FSH & LH, rarely only
LH

-MC occur in middle-aged men & women -usually are macroadenomas -symptoms MC related only to local mass effects -may cause amenorrhea or galactorrhea, ⇓ libido in
men Thyrotroph adenomas

-produce TSH ⇒ hyperthyroidism
HYPOPITUITARISM • Caused by either hypothalamic or pituitary lesions:


CORTICOTROPH ADENOMAS - MC small basophilic microadenomas that secrete ACTH Cushing’s disease -⇑ ACTH ⇒ ⇑ secretion of cortisol from the adrenal glands - moon face, buffalo hump, truncal obesity, abdominal striae -diabetes mellitus, hirsutism and amenorrhea (ACTH stimulates androgen secretion) -increased skin pigmentation (MSH is secreted with pituitary ACTH) -hypertension, muscle weakness - Diagnosis: -24 hr urine for free cortisol & 17hydroxycorticosteroids

Hypothalamic lesions: craniopharyngioma, gliomas & teratomas; metastatic carcinoma, infections Pituitary lesions: o MCCs are: nonsecretory adenomas, Sheehan’s

syndrome, radiation or surgical ablation (of ≥ 75% of the gland) o LCCs are: metastatic carcinoma, inflammatory disorders, infections, genetic defects (pit-1) • Effects: -Isolated hormone deficiencies (e.g. GH or LH) -Panhypopituitarism: in children ⇒ dwarfism & infantilism (retarded physical & sexual development) & in adults ⇒ hypogonadism, hypothyroidism & hypoadrenalism

-plasma ACTH level -dexamethasone suppression test -MRI scan
Dexamethasone Suppression Test

Pathology – Endocrine Pathology by Dr. Yabut -often

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stain negative for hormones with immunostains
SHEEHAN’S SYNDROME = Post-partum ischemic necrosis of the anterior pituitary. Precipitated by obstetric hemorrhage or shock ⇒ destruction of ≥ 75% of the gland. Pedisposing factors: -Anterior pituitary doubles in size during pregnancy -low pressure portal system unable to ⇑ blood supply -abrupt onset of hypotension ⇒ hypoperfusion ⇒ infarction. Morphology: Early: gland is swollen, soft & hemorrhagic. Later: replaced by a shrunken fibrous scar. Effects: Failure of lactation, amenorrhea, hypothyroidism, hypoadrenalism & decreased skin pigmentation. Posterior lobe: usually is not affected POSTERIOR PITUITARY SYNDROMES ADH Deficiency (Diabetes Insipidus): -⇓ ADH ⇒ decreased reabsorption of free water -urine of low specific gravity, with inability to concentrate it -polyuria, polydypsia and hypernatremia -caused by hypothalamic or pituitary lesions; idiopathic -corrected readily by ADH administration. Inappropriate ADH Secretion (SIADH): -⇑ ADH ⇒ excessive reabsorption of free water -oliguria, urine of high specific gravity, with inability to dilute it, and hyponatremia - due to a compensatory ⇑ in ANP ⇒ no hypervolemia, no ⇑ BP and no peripheral edema -neurologic dysfunction: most likely 20 to hyponatremia -MCC is ectopic ADH secretion by a small cell carcinoma of the lung -Rx: fluid restriction THYROID GLAND Embryology:

HYPOTHALAMIC (SUPRASELLAR) NEOPLASMS 1- Craniopharyngioma (MC) 2- Gliomas 3- Germ cell tumors ⇒ mass effect ⇒ hypopituitarism &/or diabetes insipidus. Craniopharyngioma: -Accounts for 3- 5% of intracranial tumors -MC in the 2nd & 3rd decades -derived from vestigial remnants of Rathke’s pouch -arise in hypothalamus, may encroach on optic chiasm -benign, contain epithelial elements, often cystic with calcification -rupture of cystic tumors ⇒ inflammatory reaction

NON-SECRETORY ADENOMAS - 20% of pituitary adenomas -MC in 4th decade of life - May grow to a large size (macroadenomas = >1 cm). - ⇒ local mass effect (headache & visual disturbances), and panhypopituitarism (hypogonadism, hypothyroidism & hypoadrenalism). Histologically: -most consist of chromophobic cells or intensely eosinophilic cells (oncocytomas) -usually are sparsely granular

-the thyroid develops from the primitive pharynx

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-the developing thyroid is attached to the base of
the tongue by the thyroglossal duct

-the thyroid descends in the midline & assumes its
final position in the anterior neck below the larynx

-excessive descent gives rise to a substernal
thyroid & incomplete descent ⇒ ectopic thyroid higher in the neck or tongue

-persistence of remnants of the thyroglossal duct
can ⇒ thyroglossal duct cyst

Effects: nervousness, warm moist skin, fine tremors, palpitations, rapid pulse, exophthalmos, weight loss, heat intolerance, muscle atrophy & weakness, osteoporosis Most Common Causes: Graves’ disease, toxic multinodular goiter, toxic adenoma Less Common Causes: -thyroiditis, struma ovarii, toxic carcinoma -TSH-secreting pituitary adenoma -overtreatment with thyroid hormone tablets (factitious hyperthyroidism) HYPOTHYROIDISM = a hypometabolic state caused by deficiency of T3 & T4. Cretinism (congenital hypothyroidism) - Clinical: severe mental retardation; short stature; coarse facial features, protruding tongue - Causes: -Endemic - due to dietary iodine deficiency -Sporadic

-thyroid dysgenesis -inherited defects in thyroid hormone
synthesis

-inherited peripheral tissue resistance to
thyroid hormone Myxedema (hypothyroidism in adults) fatigue, lethargy, slowed speech, mental sluggishness cold intolerance, weight gain, constipation ⇓ sweating, bradycardia accumulation of ECM substances (glycosaminoglycans) coarsening of facial features, nonpitting edema Causes: MCC is Hashimoto’s thyroiditis. surgical ablation or radiation iodine deficiency drugs (e.g. propylthiouracil, lithium) idiopathic primary hypothyroidism hypothalamic & pituitary disorders HASHIMOTO’S THYROIDITIS - MCC of hypothyroidism in areas where iodine intake is adequate Clinically: - seen predominately in middle-aged women -hypothyroidism with painless enlargement of the gland -may have transient thyrotoxicosis early on

Physiologic Effects of Thyroid Hormones

⇑ gluconeogenesis,

glycogenolysis, lipolysis & ATPase’s

⇒ ⇑ basal metabolic rate &

heat production

• • HYPERTHYROIDISM •= a hypermetabolic state, caused by increased
⇑ protein catabolism ⇒ muscle wasting, osteoporosis ⇑ sympathetic activity

levels of circulating T3 & T4.

Pathology – Endocrine Pathology by Dr. Yabut -familial predisposition, associated with HLA-DR3

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or HLA-DR5 Pathogenesis: -defective function of thyroid-specific suppressor T cells ⇒ emergence of helper T cells reactive with thyroid antigens -helper T cells stimulate B cells to secrete antithyroid antibodies, directed against: thyroid peroxidase, TSH-receptors, iodine transporter, & thyroglobulin, etc.

Therapy: β-blockers, propylthiouracil, potassium iodide, radioiodine ablation, surgery

-thyroid injury is mediated by complement fixing
cytotoxic antibodies, ADCC & CD8+ cytotoxic cells GOITER = enlargement of the thyroid, MC manifestation of thyroid disease - ⇓ hormone synthesis ⇒ ⇑ TSH ⇒ hyperplasia & hypertrophy of follicular cells ⇒ gross enlargement Diffuse nontoxic goiter: -endemic

-iodine deficiency -goitrogens (e.g. cabbage, cauliflower,
GRAVES’ DISEASE Clinical: -MCC of hyperthyroidism, peak incidence 20-40 y/o -a disease of females (F/M 10:1), affects 1-2% of women in US -hyperthyroidism, symmetrical thyroid enlargement -opthalmopathy and dermopathy (pretibial myxedema) -familial predisposition, associated with HLA-B8 & HLA-DR3 -Laboratory values: ⇑ T3 & T4, ⇓ TSH and ⇑ radioactive iodine uptake Pathogenesis: -An abnormality in T-suppressor cells ⇒ T-helper cells that react to thyroid Ag’s ⇒ elaboration of Bcell clones capable of producing autoantibodies reactive with TSH receptors. -IgG antibodies directed against TSH receptors, act as agonists ⇒ ⇑ thyroid hormone secretion. - The autoantibodies were originally called long acting thyroid stimulator (LATS), because the peak secretion of thyroid hormone occurs 16 hours after the exposure of thyroid tissue to antibody, compared with 2 hours for TSH. turnips, cassava root) -sporadic

-goitrogens -hereditary defect in thyroid hormone
synthesis
-Clinical: most patients are euthyroid

MULTINODULAR GOITER = nodular enlargement, derived from diffuse goiter - both monoclonal & polyclonal nodules (adenomatous goiter) Clinical: -most patients are euthyroid -mass effects: compression of trachea, vessels & nerves, & dysphagia -hyperthyroidism (toxic multinodular goiter)

-due to a hyperfunctioning nodule -not accompanied by opthalmopathy or
dermopathy * Morphology: massive enlargement (up to >2000 gm), nodules, with a mixture of hyperplastic & dilated follicles, involutional changes: hemorrhage, fibrosis, calcification & cystic degeneration

Pathology – Endocrine Pathology by Dr. Yabut -Peak incidence: 3rd-5th decades, F > M.

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-Gene rearrangement on chromosome 10 ⇒

THYROID NEOPLASMS - Solitary nodules are more likely to be neoplastic. - Nodules in younger patients (< 40 years) & in males are more likely to be neoplastic. - Most neoplasms (>90%) are benign (adenomas). - Functioning (hot) nodules on scintiscans are usually benign

constitutive expression of tyrosine kinase domain of RET protooncogene ⇒ papillary thyroid carcinoma oncogene (RET/PTC) - Often multifocal, spreads to lymph nodes in 50% of cases, but distant spread in only 5%. * Gross: unencapsulated,infiltrative, often cystic with foci of fibrosis & calcification. * Histology: papillary fronds, empty looking nuclei “Orphan Annie eye”, nuclear grooves & psammoma bodies. * Variants: encapsulated, follicular, tall cell * Prognosis: 90% survival at 20 years.

-Up to 10% of cold nodules are malignant
- Diagnosis can be made by fine needle aspiration biopsy, or else by surgical excision biopsy. THYROID ADENOMA - adenomas account for > 90% of thyroid tumors -thyroid adenomas are not premalignant Gross: a sharply demarcated solitary nodule Histology: a fibrous capsule separates the neoplastic tissue from the surrounding compressed gland. Patterns may be: trabecular (embryonal), microfollicular (fetal) macrofollicular and Hurthle cell (oncocytic) adenomas - most commonly cold (nonfunctioning) on RI-scan -rarely hot (functioning) & may cause hyperthyroidism FOLLICULAR CARCINOMA - peak incidence: 5th-6th decades, F > M. -incidence is ⇑ in areas of dietary iodine deficiency * Gross: varies from well circumscribed to extensively invasive * Histology: MC small uniform follicles containing colloid with capsular and vascular invasion (sure sign of malignancy). * Variants: trabecular, Hurthle cell - spreads widely to distant organs: bones, lungs, liver, etc. - tumor tissue may take up radioactive iodine -patients often Rx’ed postop with thyroid hormones to ⇓ TSH * Prognosis: depends on tumor stage, 25 to 45% 10yr survival rate for widely invasive tumors

THYROID CARCINOMA - uncommon in the US (~ 1.5% of all cancers). - major risk facrtor is exposure to radiation Variants include: 1- papillary carcinoma 80% 2- follicular carcinoma 15% 3- medullary carcinoma 5% 4- anaplastic carcinoma rare PAPILLARY CARCINOMA -MC form of thyroid Ca

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MEDULLARY CARCINOMA - Neuroendocrine tumor of C cells, secrete calcitonin -May also secrete: CEA, serotoin, somatostatin, VIP, ACTH, etc. - Sporadic or familial (associated with MEN IIa & IIb, etc., in 20% of cases) - Familial cases are associated with germ line mutations in RET * Gross: sporadic cases: discrete tumor in one lobe, peak incidence 5th-6th decades. MEN-associated: multicentric & bilateral , peak 3rd-4th decades * Histology: cell nests or trabeculae, amyloid deposits in the stroma, C cell hyperplasia, + for calcitonin, chromogranin, - for thyroglobulin * Prognosis: overall 5-yr survival rate is 60 to 80%, survival rates are better in familial cases due to screening programs, serum calcitonin & CEA levels are monitored post-op

situated in close proximity to the upper and lower poles of each thyroid lobe - Histology: composed of chief cells (the majority) and fat cells. The chief cells may undergo transition to oxyphil cells (mitochondria), and water clear cells (glycogen). - chief cells secrete PTH -secretion of PTH is regulated by the level of free Ca++ -⇑ PTH secretion ⇒ ⇑ serum Ca++ by: 1. increasing synthesis of 1,25-(OH)2D, thus enhancing absorption of calcium from GIT. 2. activating osteoclasts ⇒ mobilizing calcium from bone 3. increasing renal tubular reabsorption of calcium while increasing urinary phosphate excretion -Causes of hypercalcemia: - autonomous PTH hypersecretion - osteolytic metastases - PTH-related protein (PTHrP)

PARATHYROID GLANDS - There are usually four glands (they can be as many as 12), weighting 30 to 40 mg each,

PRIMARY HYPERPARATHYROIDISM = autonomous hypersecretion of PTH. - Accounts for up to 90% of cases of hypercalcemia. - Peak incidence 6th decade & older, F > M. - Most cases are sporadic, but few cases are familial (associated with MEN I & MEN IIA) Causes: 1- Parathyroid adenoma (80%), 2- Primary hyperplasia (15%), 3- Carcinoma (<5%) * Morphology: • Adenoma

-solitary & encapsulated, may consist of any of
the 3 cell types

-remaining glands are normal to ⇓ in size

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-may be in an ectopic location
• Hyperplasia

-classically all 4 glands are involved -may be nodular or diffuse
• Carcinoma

-hyperplasia of all (4) parathyroid glands -skeletal changes of “renal osteodystrophy” -metastatic calcification

-solitary, dense capsule, may exceed 10 gm -cytologic features are not reliable, presence of
invasion or metastases required to make Dx * Clinical Features: - asymptomatic 90% are asymptomatic & discovered on routine blood tests Ca++ & PTH levels are ⇑ symptomatic - 10% are symptomatic - osteitis fibrosa cystica - bone pain, pathologic Fx’s - ⇑ bone resorption with expansile areas (brown tumors) - nephrolithiasis - metastatic calcification - GI Sx’s: constipaton, nausea, peptic ulcers, pancreatitis - CNS Sx’s: depression, lethargy, seizures - NM Sx’s: weakness, fatigue

* Clinical: few cases develop “tertiary” hyperparathyroidism, looks identical to primary hyperplasia HYPOPARATHYROIDISM = PTH deficiency & hypocalcemia -neuromuscular irritability (tetany): carpopedal spasm, laryngospasm, mental status changes, convulsions -cardiac conduction abnormalities -calcification of the eye lens (cataract) -calcification of the basal ganglia (Parkinsonism), ⇑ ICP (headache & papilledema). -MCC: surgical excision of all glands (during total thyroidectomy). -LCC: congenital parathyroid agenesis (DiGeorge’s syndrome), primary (idiopathic) atrophy autoimmune damage -Lab. data: ⇓ serum Ca++ & ⇓ serum PTH level.

PSEUDOHYPOPARATHYROIDISM (PHP)
= Hypocalcemia and hyperphosphatemia, with: -⇑ serum levels of PTH with hyperplasia of the parathyroid glands -no osteitis fibrosa cystica -no vitamin D deficiency or renal failure. * Pathogenesis: end-organ resistance to PTH, i.e. kidneys & bone do not respond to PTH stimulation. * Clinical Features: similar to hypoparathyroidism (tetany, etc.) o PHP type 1 - ⇓ cyclic AMP response to PTH (deficiency of Gsα ) short stature, round face, short neck, short metacarpals & metatarsals (Albright hereditary osteodystrophy). PHP type 2 - normal cyclic AMP response to PTH, but with ⇓ response to cyclic AMP, phenotypically normal

o

SECONDARY HYPERPARATHYROIDISM = Compensatory hypersecretion of PTH due to hypocalcemia -renal failure -vit. D deficiency * Morphology:

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PSEUDOPSEUDOHYPOPARATHYROIDISM - In PHP type 1, other family members may exhibit the physical features of Albright hereditary osteodystrophy (short stature, round face, short neck, short metacarpals & metatarsals) but are metabolically normal, with normal serum calcium & normal PTH, i.e. false (pseudo) pseudohypoparathyroidism. - Composed of two distinct units: steroid secreting cortex & catecholamine producing medulla - In the adult, the normal adrenal weighs 4 gm. - The cortex consists of three functional zones: 1 - zona glomerulosa 2 - zona fasciculata (75% of the cortex) 3 - zona reticularis - The cortex secretes three types of steroid hormones: 1 - mineralocorticoids (aldosterone) - zona glomerulosa. 2 - glucocorticoids (cortisol) - zona fasciculata mainly. 3 - sex steroids (testosterone) - zona reticularis mainly.

ADRENAL GLAND

Cortisol: -regulated by ACTH (& hypothalamic CRH) -inhibits release of CRH & ACTH -circulates in the blood bound to plasma proteins -free unbound cortisol is physiologically active & enters target cells by diffusion -binds to cytoplasmic receptors, then translocated into the nucleus where it binds to hormoneresponsive elements altering expression of specific genes. * Biologic effects:

-⇑ gluconeogenesis & ⇓ uptake of glucose by fat &
muscle

-⇓ protein synthesis & ⇑ protein degradation -⇑ vascular tone & some mineralocorticoid
activity

-anti-inflammatory & immunosuppressive effects
Aldosterone: - Accounts for 95% of mineralocorticoid activity. -regulated by renin-angiotensin & potassium levels. -aldosterone promotes reabsorption of sodium and excretion of potassium. -excess aldosterone ⇒hypernatremia & hypokalemia ⇒ hyper-volemia ⇒hypertension. Testosterone: -Excess testosterone in females causes defemenization & virilization; (hirsutism, acne, amenorrhea, clitoral enlargement, atrophy of the breasts & uterus, deepening of the voice & frontal balding).

Pathology – Endocrine Pathology by Dr. Yabut -In boys, excess testosterone leads to precocious

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puberty. DISEASES OF ADRENAL CORTEX Hyperfunction (hyperadrenalism): Cushing’s syndrome Hyperaldosteronism Adrenogenital syndromes Hypofunction (hypoadrenalism): - Acute (e.g. Waterhouse-Friderichsen Syndrome) - Chronic:

* Diagnosis: 24 hr urine free cortisol, plasma ACTH, Dexamethasone Suppression Test PRIMARY HYPERALDOSTERONISM = excessive secretion of aldosterone independent of renin-angiotensin system. * Features: hypervolemia, hypokalemia, hypertension, low renin * Causes: -MCC is aldosterone-secreting adenoma (Conn’s syndrome) in 80% of cases -Bilateral idiopathic hyperplasia (? due to an abnormal secretagogue) -Glucorticoid-suppressible hyperaldosteronism: hybrid cells produce both cortisol & aldosterone, ⇑ aldosterone under influence of ACTH, suppressible by administration of dexamethasone * Prognosis: adenomas are curable by surgery. ADRENOGENITAL SYNDROMES Adrenogenital syndromes (ambiguous genitalia & virilism in females, and precocious puberty in males) can be caused by: 1- Androgen-secreting adrenal cortical neoplasms. 2- Congenital Adrenal Hyperplasia (CAH): -corticosteroid biosynthetic defect -MC 21-hydroxylase deficiency (90% of cases; autosomal recessive) ⇒ ⇓ cortisol ⇒ ⇓ feedback inhibition of ACTH ⇒ ⇑ ACTH levels ⇒ bilateral adrenocortical hyperplasia -aldosterone synthesis is MCly affected as well ⇒ salt wasting adrenogenitalism (⇓ Na+, ⇑ K+, hypovolemia) -⇑ production of androgens

- primary (due to adrenal cortical
insufficiency, e.g. Addison’s disease)

- secondary (due to ACTH deficiency) - tertiary (rarely - due to hypothalamic CRH
deficiency).

CUSHING’S SYNDROME Etiology: 1- Exogenous: high dose cortisone therapy (MCC). 2- Pituitary hypersecretion of ACTH (Cushing’s disease), accounts for 70% of endogenous hypercortisolism. Associated with hyperpigmentation of the skin (↑ MSH). 3- Autonomous hypersecretion of cortisol by an adrenal adenoma, carcinoma or primary hyperplasia (i.e. ACTH independent). 4- Ectopic production of ACTH or CRH by nonendocrine neoplasms (bronchogenic small cell carcinoma). * Clinical features: truncal obesity, moon face, hirsutism, cutaneous striae, muscle weakness, osteoporosis, hypertension & hyperglycemia; Changes are reversible if the cause is corrected. * Morphology: •Cushing’s disease: ACTH is elevated ⇒ adrenals are bilaterally hyperplastic. Changes are the same with ectopic ACTH or CRH. •Adrenocortical neoplasms: uninvolved adrenal cortex is usually atrophic due to ACTH suppression.

•Adenomas are small & cytologically bland
appearing

•Carcinomas are large & often anaplastic

Pathology – Endocrine Pathology by Dr. Yabut -Composed of specialized neuroendocrine

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(chromaffin) cells, and is the major source of catecholamines: epinephrine & norepinephrine. -Chromaffin cells secrete catecholamines in response to signals from preganglionic sympathetic nerve fibers. -These cells can also secrete a wide variety of bioactive amines and peptides, such as: histamine, serotonin, & neuropeptide hormones. -Clusters of similar neuroendocrine cells form the extra-adrenal paraganglia - closely associated with the autonomic nervous system. -The branchiomeric (carotid bodies) & intravagal paraganglia are parasympathetic, and the aorticosympathetic (organs of Zuckerkandl) are sympathetic. ACUTE ADRENOCORTICAL INSUFFICIENCY MCC is sudden withdrawal of corticosteroids in cases of long-term steroid therapy, or destruction of adrenals by massive hemorrhage PHEOCHROMOCYTOMA = neoplasm composed of chromaffin cells that secretes catecholamines (0.1 - 0.3 % of all cases of hypertension) * The “10 %” tumor:

Waterhouse-Friderichsen syndrome:
-overwhelming meningococcal septicemia -DIC with widespread purpura (esp. skin) -rapidly progressive hypotension ⇒ shock -massive bilat. adrenal hemorrhage ⇒ acute

•10 % extra-adrenal •10 % familial •10 % in children •10 % bilateral in sporadic cases, but 70%
bilat.in familial cases

adrenocortical insufficiency -? causes of adrenal hemorrhage: DIC, endotoxininduced vasculitis, bacterial seeding of small vessels -high mortality rate CHRONIC ADRENOCORTICAL INSUFFICIENCY * Primary (adrenal) or secondary (hypothalamic/pituitary): Primary (Addison’s disease): MCC: autoimmune adrenalitis; tuberculosis, metastatic cancers (⇒ destruction of ≥ 90% of the cortex) ⇒ decreased cortisol & aldosterone, with feed-back elevation of ACTH (+ MSH) ⇒ hyperpigmentation of skin, ⇑ K+, ⇓ Na+, ⇓ BP, weakness, anorexia, N&V, hypoglycemia Secondary: to hypothalamic or pituitary lesions associated with decreased ACTH ⇒ bilateral adrenal cortical atrophy, sparing the zona glomerulosa (skin color is pale and aldosterone is normal, i.e. no sodium or potassium abnormalities). ADRENAL MEDULLA

•10 % malignant in adrenal cases, but up to 40%
malignant in extra-adrenal cases * Clinical effects: hypertension (paroxysmal), tachycardia, arrhythmias, tremors, sweating, sense of apprehension, attacks can be fatal * Diagnosis: 24 hour urine for catecholamines; or metanephrines & vanillylmandelic acid (VMA)

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plus 4- Ganglioneuromas of the skin, eyes and mucous membranes of the mouth, GI tract, respiratory tract & bladder (100%) 5- Marfanoid body habitus (65%) ------------------------------------------------------------------------Aanhin pa ang damo, Kung sayo plang, may tama na ako? I list my number…. Can I have yours? Nagpapacute kba? Kc umeepekto eh! Kulangot kba? Kasi I wanna take you out. Hi, I’m yours, can I call you mine? --- galing sa old trans ng acute abdomen! just to have some good memories to remember about the exam. hehehe LOVE is just a word until someone you meet gives it a proper meaning. Happy Valentines! ööö

MULTIPLE ENDOCRINE NEOPLASIA: MEN I (Wermer’s Syndrome) - heritable disorder caused by loss of a tumor suppressor gene on chromosome 11. 1. Parathyroid hyperplasia or adenoma (95%) ⇒ ⇑ Ca++ 2. Pancreatic Islet Cell tumors (75%) ⇒ excessive secretion of: - gastrin ⇒ peptic ulcers (Zollinger-Ellison syndrome) - insulin ⇒ hypoglycemia - serotonin ⇒ carcinoid syndrome - VIP ⇒ watery diarrhea 3. Pituitary adenoma (66%); MC prolactinoma, also GH & ACTH producing adenomas MEN IIA (Sipple’s Syndrome) - inherited mutation in the RET protooncogene on chromosome 10. 1. C cell hyperplasia or Medullary thyroid carcinoma (100%) 2. Pheochromocytoma (50%), often bilateral and may arise in the extra-adrenal paraganglia 3. Parathyroid hyperplasia or adenoma (25%) MEN IIB (Gorlin’s Syndrome) -inherited mutation in the RET protooncogene on chromosome 10, different from that seen in MEN IIA -neoplasms are as in MEN IIA: 1- C cell hyperplasia or Medullary thyroid carcinoma (100 %) 2- Pheochromocytoma (34%) 3- Parathyroid hyperplasia or adenoma (4%)

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