Endocrine Pathology

Pituitary Gland Pathology

1. ANTERIOR Pituitary :

 Secretes trophic hormones (trophic mean target another gland to secrete another hormone)

 Acidophil cells (pink in color); somatotroph, prolactin

 Basophil cells (blue in color); corticotroph, gonadotroph, thyrotroph.

 Under influence of feedback; +ve from hypothalamus and -ve from the body.  Most are stimulatory factors except for prolactin.

 Most diseases arise from the pituitary itself (not hypothalamus)



FUNCTIONING Abnormality :

A) Hyperpituitarism :

 Excessive secretion of one or more of hormones.

 Most common cause: functional adenoma (benign tumor).

Then: hyperplasia, carcinoma, exogenous source (like from therapy)  Few adenomas are bilineage (GH + prolactin)

B) Hypopituitarism :

 Deficiency of one or more of pituitary hormones.  Damage to more than 75% of anterior pituitary gland.

 Most common cause: non-functional adenoma (it might be not-synthesizing or non-secretory)

Others: congenital dysgensis, ischemia (specific to pituitary called;

Sheehan syndrome occur post-partum), surgery, radiation, inflammatory

diseases (ex. Sarcoidosis), bone diseases.

 Pituitary tumors causes damage to optic nerve (bitemporal heianopsia) and increase intracranial pressure (headache, nausea, vomit)



Pituitary adenoma :

 Classified according to the cell origin, with corresponding hormonal synthesis.  Mostly develop in middle aged adults (30-50 years).

 75% functional, secreting (one or more hormone) 25% functional, silent (synthesizing but not-secreting) rarely hormone negative (non-synthesizing at all)

 Most are sporadic, 3% are syndromic (multiple endocrine neoplasia).

(sporadic mean come in individual, no family Hx and it won’t pass to the 2nd

generation)

 <1 cm called micro-adenoma (symptom related to the secretion)

>1 cm called macro-adenoma; (symptom related to the mass; optic nerve damage ‘bitemporal heianopsia’ & increased intracranial pressure ‘headache, nausea, vomit’ )



 Up to 20% of healthy adults have silent micro-PA (3 mm).

 Pathogenesis :

- Mutation in G-proteins that transmit a signal transduction to intracellular effectors (adenyl-cyclase), generating 2nd _{messengers cAMP, a potent}

mitogenic factor.

- Normally, G-proteins are activated upon ligand binding.

- Mutant G-proteins have autonomous, permanent activity (activation without ligand).

A) Prolactinoma  Most common PA.

 Cau ses

galactorrhea, amenorrhea, loss of libido and infertility.

 Symptoms appear obviously in menstrual and premenopausal women than in men and postmenopausal women

 Stalk effect: any interruption in hypothalamus-pituitary axis would cause

prolactinoma.

B) Growth Hormone-Producing Adenomas  Second most common

 Secrete little amount of GH, at the time of symptoms it mean the adenoma is advanced = large.

 Very Big + Functional adenoma = most likely it is related to growth hormone adenoma.

 GH stimulates secretion of insulin-like growth factor-1 from liver.

 Gigantism in children, Acromegaly in adults (face, hands, feet, soft tissue).  Also develops hypertension, heart failure, diabetes.

C) Corticotroph Cell Adenomas

 Most are small at the time of diagnosis

 very sensitive (secrete small amount of hormone causing symptoms in

contrast to GH-adenoma)

 CUSHING DISEASE: bilateral adrenal enlargement.

 NELSON SYNDROME: develop after bilateral adrenalectomy (no negative

feedback from the body), clinically aggressive.

 Hyperpigmentation characteristic for CCA because ACTH & MSH share precursor

D) Thyrotroph & Gonadotroph

 Rare, Produce little amount of hormones, usually symptoms are related to mass effect.

2. POSTERIOR Pituitary

 Secretes anti diuretic hormone (ADH), Acts on kidneys to promote reabsorption of water.

 ADH deficiency is called DIABETES INSIPIDUS (polyuria, polydipsia, dilute urine, hypernatremia), caused by head trauma, tumors or surgery.

 Excessive ADH is called SIADH (hyponatremia causing brain edema which may lead to death), mostly secondary to paraneoplastic syndrome (small cell

carcinoma of lung; because they secrete ADH).

Thyroid Gland Pathology



 It is elevation of circulating free T3 and T4 leading to Hypermetabolic state.  Mostly secondary to hyperthyroidism (increased function of thyroid gland),

less common: exogenous source (as intake of thyroid drug) or thyroiditis  Causes :

Associated with hyperthyroidism Not associated with hyperthyroidism ˃ Primary :

1) Diffuse toxic hyperplasia (Graves Diseasea)

2) Hyper-functioning (toxic) multinodular goiter

3) Hyper-functioning (toxic) adenoma

1) Subacute granulomatous thyroiditis (painful)

2) Subacute lymphocytic thyroiditis (painless)

3) Struma ovarii “ovarian teratoma with thyroid tissue also called ectopic thyroid”

4) Factitious thyrotoxicosis (exogenous thyroxine intake)

˃ Secondary :

1) TSH-secreting pituitary adenoma “rare”

 Symptoms :

- Heat intolerance, excessive sweating. - Skin: soft, flushed, warm

- Muscles (characteristic): proximal upper and lower muscle weakness. - Cardiac (most dangerous): arrhythmia, palpitation.

- GIT: soft diarrhea, malabsorption, weight loss.

most obvious in Grave’s disease, secondary to accumulation of soft tissue behind the eye globes - Ocular: lid lag, wide staring eyes (most obvious in Grave’s disease)

- Apathetic hyperthyroidism: asymptomatic, in elderly because there metabolism is normally low, only diagnosed by blood test.

- Extreme situation called Thyroid storm = life-threatening.

B) Hypothyroidism :

 Low level of circulating T3 & T4 leading to hypometabolic state.

 Very important to check pregnant women (cause the baby depend on his mother thyroid) and the baby at birth for thyroid function because it may lead to mental retardation

 Cretinism: infants or early childhood (low iodine, inborn enzymatic errors), impaired skeletal, mental retardation, short stature, coarse faces, protruding tongue.

 Myxedema: adult, cold intolerance, bradycardia, heart failure, constipation,

weight gain, slow mental process, apathy, anemia.  Causes :

˃ Primary

1) Post-ablative: surgery, radioiodine therapy or external radiation. 2) Hashimoto thyroiditis*

3) Iodine deficiency*

4) Dyshormonogenetic goiter (Congenital biosynthetic defect)* 5) Drugs: lithium, iodides, p-aminosalicyclic acid*

6) Thyroid dysgenesis (Rare developmental abnormalities of the thyroid) - Post-ablative & Hashimoto thyroidism are the vast majority of

hypothyroidism cases in adequate dietary iodine region.

- * = Associated with enlargement of thyroid (goitrous hypothyroidism) ˃ Secondary



 Autoimmune disease  Peak incidence 45-65

 10 times more in women than in men because autoimmune diseases more prevalent in females

 Pathogenesis

- Progressive depletion of epithelial cells, replaced by inflammatory cells (lymphocytes and plasma cells).

- Abnormality begin with; Autoreactive CD4+ T-lymphocytes against normal thyroid antigens → produces INF-γ → Recruitment of macrophages, CD8+ T lymphocytes, causing damage to epithelium.

- Also activate plasma cells of B-lymphocyte to synthesize auto antibodies (diagnosis by the AB)

On the left; pink follicle (Hurthle cell) On the right; germinal center

 Clinical

- Painless goiter

- Initial transient phase of thyrotoxicosis . Followed by gradual, progressive

hypothyroidism.

- Risk of B-cell lymphomas but NOT thyroid carcinoma.

- Other autoimmune diseases are common (like; lopus arthritis, immune gastritis, …)

 Morphology

- Grossly: diffuse enlargement of thyroid gland, Intact capsule, Not

adherent to adjacent structures.

- Micro: dense infiltration of B-lymphocyte (forming germinal centers), plasma cells, T-lymphocytes and macrophages.

- Follicular epithelium is atrophic, show metaplastic changes into larger, pink cuboidal cells (full of mitochondria) called HURTHLE CELLS or OXYFIL CELLS - With disease advance: fibrosis and atrophy.



Grave’s disease

 Most common cause of hyperthyroidism

 Autoimmune disease

 20-40 years, females 7 times more than males.

 Triad: thyrotoxicosis, ophthalmopathy, localized infiltrative dermatopathy (called pretibial myxedema, minority of patients)

 Genetic predisposition (family history, HLA-DR3 and B8, other autoimmune diseases

 Transient episodes of hypothyroidism within the course of the disease.



- Break in CD4 tolerance against normal thyroid antigens → Activates mainly B-lymphocytes to secrete auto antibodies, Also responsible for the

a) Thyroid-stimulating immunoglobulin (TSI): most important, auto-AB that binds TSH receptor and mimics action of TSH, stimulating adenylyl cyclase, results in secretion of thyroid hormones (specific) b) Thyroid growth-stimulating immunoglobulins (TGI): another AB

against TSH receptor, stimulates proliferation of follicular epithelium = goiter

c) TSH-binding inhibitor immunoglobulins (TBII): prevents TSH from normal binding to its receptor and:

I. stimulates proliferation of follicular epitheliem, II. other forms inhibit thyroid function (coexist)

That’s why grave’s disease may have episode of hypothyroidism. d) Anti-thyroglobulin, anti-thyroid peroxidase Abs (not specific)

related to hashimito dis.



- Increased size of extra orbital muscles and retro orbital soft tissue causing exophthalmos by:

a) Infiltration by inflammatory cells b) Inflammatory edema

c) Accumulation of extracellular matrix (hyaluronic acid and chondroitin sulfate)

d) Increased fat cells

- Exophthalmos is irreversible even post treatment

 Morphology:

- Diffuse goiter, soft, non-adherent, intact capsule

- Micro: follicular epithelial cells are hyperplastic (tall columnar, crowded→ formation of small papillae, project into follicular lumen, lack fibrovascular cores)

- Colloid is pale, scalloped margins

- Lymphoid infiltrate in between the cells (T > B-cells & plasma cells), germinal centers

- Skin: edema, lymphocytes, glycosaminoglycans (hyaluronic acid and chondroitin sulfate)



 Most common 30-50 year old.

 Viral infection or post viral inflammation (history of upper respiratory tract infection)

 Self-limited, not progressive.  Clinical & Morphology :

- Acute painful goiter, could be asymmetrical, not adherent. - Fever, malaise, transient hyperthyroidism, leukocytosis.

- Micro: disruption of thyroid follicles, infiltration begin by granulocytes → followed by lymphocytes, plasma cells and macrophages

- (different than hashimoto they do not form germinal center)

- Extravasated colloid initiates foreign body reaction → forming granulomas



auto immune, initial thyrotoxicosis then euthyroid, return in future pregnancies.

 Diagnosis is clinically

 Micro: lymphocytic infiltrate, germinal centers and NO Hurthle cells.



 Rare, chronic, Unknown etiology, autoimmune??

 Progressive fibrosis of thyroid and surrounding structures (adherent)  Hard goiter mimicking cancer.

 Associated with fibrosis in other organs (retroperitoneum as pancreas, kidney, Aorta)

 Micro: thick fibrous bands, minimal follicles



 It is result from Vigorous clinical palpation of the thyroid gland.

 Results in multifocal follicular disruption associated with chronic inflammatory cells and occasional giant-cell formation

 Unlike de quervain thyroiditis, abnormalities of thyroid function are not

present, and palpation thyroiditis is usually an incidental finding in specimens resected for other reasons

 Asymptomatic.



 Reflects impaired synthesis of thyroid hormones, Commonly caused by iodine deficiency.

 Leads to compensatory rise in TSH causing hypertrophy & hyperplasia of follicular epithelium → goiter → euthyroid.

 Endemic goiter: it is 10% or more of population has goiter, in areas where soil,

water and food contain little iodine (Himalaya).

 Sporadic goiter: mostly idiopathic, others: excessive calcium, cabbage,

 Clinical :

- The main complaint is mass in the neck (cosmetic, stridor, dysphagia, compression of vessels)

- Not adherent

- Plummer syndrome: when toxic nodule produces hyperthyroidism (no ocular disease)

- Some patients have hypothyroidism

- So, it can be euthyroid, hyperthyroidism or hypothyroidism.  Morphology :

- Early: diffuse goiter, similar to Grave’s disease

- When euthyroid status is reached, TSH decreases, follicular epithelium becomes small and flat, with predominance of colloid (colloid nodule). - Normally: follicular epithelial cells are heterogeneous in response to TSH

(some respond more than others)

- With repeated attacks, proliferation is variable, fibrosis, hemorrhage, cystic degeneration, calcification goiter is irregular (multinodular goiter)

- Some nodules become dominant & secrete excess hormones (toxic nodule) - Both mono & polyclonal nodules are present.



Benign tumors : Follicular adenoma

 Benign neoplasm of follicular epithelium  Solitary (resemble the toxic nodule)  Mostly non-functional (cold nodule)

 Clinically and radiology Might be difficult to distinguish from hyperplastic (toxic) nodule or carcinoma, the diagnosis is by pathology (under the Microscope).

 Pathogenesis :

a) Activating mutation in TSH receptor or α-subunit causing overproduction of cAMP  cell growth and mitosis

Rarely, can be functional and produce hyperthyroidism

b) 20% of cases have RAS mutation (also present in 50% of carcinoma)  Morphology :

- Solitary, well demarcated mass with intact, thin capsule (not present in hyperplastic nodules)

- Micro: uniform follicles contain colloid distinct from the rest of thyroid, cells are uniform

- If follicular cells show Hurthle cell change, called Hurthle cell adenoma - Atypia might be present, but does not mean malignancy (Atypia is normally

common in endocrine system)



Thy

roid

Carcinoma :

 Rare, Early adulthood, women (estrogen receptors)

 Old and pediatric cases might occur, risk factors (radiation)

 Types; Papillary carcinoma, follicular carcinoma, Medullary carcinoma & Anaplastic carcinomas.

 All derived from the follicular epithelium, except for medullary carcinomas (C-cell)

A) PAPILLARY CARCINOMA

o Most common thyroid carcinoma (75 - 85%)

o Arise at any age (mostly middle aged women) o Painless mass in neck, Solitary or multiple o History of previous ionizing irradiation

o Commonly associated with local LN metastasis (does not affect the prognosis) o Indolent disease with 10 year survival >95% (one of the best human cancer

in prognosis) o Pathogenesis

- 2 pathways, end by activating mitogen activating protein (MAP) kinase signaling pathway:

Orphan Annie eye II. 20% of patient have mutation in RET gene rearrangement (tyrosine

kinase receptor), creating novel gene (ret/PTC) which activates RET and MAP.

III. 10% Neurotropic tyrosine kinase receptor1 (NTRK1) mutation. o Morphology (important)

- Well circumscribed, sometimes encapsulated - Micro: special nuclear features:

 Optically clear nuclei, called ground glass or Orphan Annie eye  Nuclear grooves (pseudo-inclusions) like coffee bean

- Papillary architecture; Tip of papillae because it far from blood vessel may have ischemia and Calcification (psammoma body), cysts are common B) FOLLICULAR CARCINOMA

o o Second most common carcinoma (10- 20%) o Older age than PTC.

o Associated with; iodine deficiency & RAS mutation in 50%

o Micro: normal looking follicles, may see Hurthle cells, capsular or lymphovascular invasion.

Evaluating the integrity of the capsule is critical in distinguishing follicular adenomas from follicular carcinomas.

C) MEDULLARY CARCINOMA (5% )

o Neuroendocrine neoplasm, arises from parafollicular cells (C-cells) o Increased blood level of calcitonin (but no hypocalcemia)

o Sporadic in 80% of cases, old age

o 20% are familial (familial medullary thyroid carcinoma, or multiple endocrine neoplasia), young age, aggressive disease, bad prognosis

o RET gene mutation o Morphology

- Solitary tumor (sporadic) or multiple (familial) - Micro: polygonal or spindle cells.

- Secrete amyloid (derived from calcitonin), positive for congo-red stain - C-cell hyperplasia is in non-tumorous areas

D) ANAPLASTIC CARCINOMA o Rare disease (<5% )

o Old age

o History of multinodular goiter or PTC o P53 mutation

o Very aggressive (one of the worst carcinoma)

o Rapid growth and death within a year o Cells are large, epithelioid or spindle,

pleomorphic

Parathyroid Gland Pathology

 Most tumors are active, diagnosis is made after noticing hypercalcemia but asymptomatic

 PRIMARY HYPERPARATHYROIDISM :

 Very common

 Causes silent hypercalcemia (in contrast to cancer) , incidentally finding.  80% of cases are secondary to adenoma (in one of the 4 parathyroid the rest

are atrophic),

15% hyperplasia (four glands), 5% carcinoma.  95% cases are sporadic, 5% familial (MEN)

 Familial hypocalciuric hypercalcemia: rare disease, mutation in Ca sensing

 Pathogenesis

- Parathyroid adenomatosis gene1 (PRAD1), cyclin gene.

- Cyclin D1 (another cyclin) in adenoma, hyperplasia and carcinoma. - MEN1 gene (tumor suppressor) it mutation lead easy tumor progression.  Morphology

- Under the microscope they are identical, different in; how many gland affected & weight.

- Adenoma: single large glands, the rest are atrophic, composed predominantly of Chief cells, may show atypia, weight 0.5-5 gm

- Hyperplasia: more than one gland, chief cells, the combined weight usually less than 1 g

- Carcinoma: single, adherent to neck, shows invasion, metastasis, weight >5 g

 SECONDARY HYPERPARATHYROIDISM :

 Develops in patients with long standing hypocalcemia.

 Most commonly seen in chronic renal failure (hyperphosphatemia suppresses calcium level & also no activation of vitamin D → no absorption of calcium from guts)

 Morphology: hyperplasia of the four glands, serum calcium then normalizes  If patient develop progressive and autonomous hypercalcemia (usually even

after a correction of the kidney by transplantation) it is called tertiary hyperparathyroidism

 HYPOPARATHYROIDISM  Rare

 Results from surgical removal, congenital absence, autoimmune, fungal infection

 Patients develop hypocalcemia (muscle weakness, neuromuscular abnormality)

Endocrine Pancreas Pathology

 Diabetes mellitus: group of diseases that share a common feature of persistent hyperglycemia.

 Defect in insulin secretion, function or both resulting in damage to multiple organs in the body.

 Commonly cause; end-stage renal failure, adult onset blindness & non-traumatic L-limb amputation.

 INSULIN FUNCTIONS

- Increase uptake of glucose in skeletal, cardiac muscles (stored as glycogen) and adipocytes (stored as fat), both forming 2/3 of body weight.

- Inhibit fat & glycogen degradation - Reduce production of glucose from liver

- Promote amino acid uptake into muscles & protein synthesis, inhibit degradation

- Promote DNA synthesis, cell growth & differentiation - In fasting state, insulin is low

 Type 1 DM

 Characterized by an absolute deficiency of insulin secretion caused by pancreatic β-cell destruction, usually resulting from an autoimmune attack (insulitis) → Break in tolerance to β-cells or insulin

 10% of all cases.

 Begins in childhood, manifests in adolescence (abrupt onset)  Genetic predisposition HLA-DR3 and HLA-DR4

 CD4-T lymphocytes, secrete INF-γ → activate CD8-T lymphocytes & macrophages (secrete IL-1, TNF) → damage β-cells, also activate B-lymphocytes to produce auto AB against insulin or β-cells

 Micro: β-cell necrosis & lymphocytes infiltration (insuliti))  T-cell inhibitory receptor (CTLA-4)

 Viral infection

 Type 2 DM

 Caused by a combination of peripheral resistance to insulin action and an inadequate compensatory response of insulin secretion by the β cells ("relative insulin deficiency").

 80% to 90% of cases.

 Genetic + environmental (dietary habit)

 Genes not related to immune tolerance or insulin signaling pathway (still unknown)

 Insulin resistance precedes DM by decades  Obesity is strongly associated with DM

 ↑ secretion of resistin and free fatty acid from adipocytes in obese (causing insulin resistance)

& Decreased adiponectin secretion (insulin sensitizer) in obese

 Thliazolinediones drug family activates PPARγ gene in fat cells & reverse the abnormalities

 FFA & hyperglycemia adversely affects β-cells both qualitatively (loss of normal response to glucose ingestion) and quantitatively (loss of β-cells & deposition of islet cell amyloid (amilin)

 Monogenic DM :

 A single genetic mutation causing DM (in contrast to most cases of types 1,2 are genetically complex (multiple susceptible foci)

 Rare

 Either affect β-cell function (MODY genes) or cellular insulin signaling  Other causes of DM

 Loss of pancreatic tissue (carcinoma, fibrosis)

 Increased hormones antagonizing insulin: (GH, cortisol, glucagon, thyroxin, adrenalins)

 CMV, Coxsackie B pancreatitis

 Syndromes: Down, Kleinfelter, Turner

 Gestational diabetes (increased insulin requirement on a background of resistance)

 Drugs; β-agonists (causing hyperglycemia)



1. Non-enzymatic glycosylation of proteins (sticking or adhering of glucose to protein)

a) Glycated hemoglobin (HgA1C): reflects history and degree of

hyperglycemia, because normally there is a low element of glycation, which will rise in DM patient to >6% of total Hb, more rising the worse is the hyperglycemia.

b) Glycated extracellular matrix in vessels: collagen will have permanent changes (cross linking), called advanced glycosylation end products (AGEs), causing entrapment of plasma proteins (lipoproteins), causing accelerated atherosclerosis.

c) In renal glomeruli, glycated basement membrane → becomes thickened & entraps albumin.

d) glycated serum proteins are entrapped in endothelium, causing release of cytokines & growth factors. In the kidney, causes increased endothelial permeability, mesangial proliferation & synthesis of extracellular matrix. 2. Activation of protein C

o Secondary to cytoplasmic hyperglycemia

o Activated protein C produces transforming growth factor (TGF-β), causing angiogenesis

o Increased deposition of extracellular matrix and basement membrane o critical in retina = blindness

3. Intracellular hyperglycemia with disturbance in polyol pathways o Important in organs that are insulin independent (brain, nerves, vessels,

lens, kidneys)

o Intracellular glucose is metabolized into sorbitol & fructose → increasing intracellular osmolality & water influx → swelling



PANCREATIC ENDOCRINE NEOPLASMS

 PEN, or islet cell tumor  2% of pancreatic tumors  Present in adulthood  Single or multiple

 Functional or non-functional

 Benign (commonly <2 cm) or malignant (metastasis to LN and liver) A) Insulinoma

 β-cell tumor, most common PEN.  90% are benign, solitary, functional.

 Recurrent attacks of hypoglycemia, affecting CNS, precipitated by fasting & exercise.

 Micro: proliferation of islets of neuroendocrine cells, uniform and monotonous

(similar to normal cell even in malignant, no anaplasia, differentiate by function or stain).

 Positive for insulin immunohistochemically stain (brown in color)

B) Gastrinoma

 Produced by gastrinoma triangle: pancreas, peripancreatic soft tissue & duodenum.

 90% of patients develop severe, multiple peptic ulcers (Zollinger-Ellison syndrome), refractory to ordinary therapy

 50% show invasion & metastasis, 25% are syndromic (MEN 1) & multiple.  Similar histology to insulinoma

C) Glucagonoma  α-cell tumor

 Increased serum glucagon resulting in mild diabetes.  Most common in peri & post-menopausal women

 Commonly have characteristic skin rash (necrolytic migratory erythema) mostly in face, U-limb

 Unknown cause, a theory; deficiency in nutrient secondary to increase glucagon mostly the zinc.

 Similar histology to insulinoma

Adrenal Gland Pathology

A) The Zona Fasciculate; Hypercortisolism :

 Increased glucocorticoid levels in blood

 Most common cause: exogenous administration then; Corticotroph pituitary adenoma (Cushing disease), Primary adrenocortical hyperplasia,

 Cushing syndrome

o Primary adrenocortical origin

o Elevated serum cortisol and low ACTH

o Most common cause is unilateral adrenocortical neoplasm o Primary bilateral hyperplasia is rare, 2 types:

- Macro-nodular growth (>3 mm) usually acquired later in life - Micro-nodular, pigmented, familial (early in life), other endocrine

hyperplasia

 Ectopic ACTH :

o Paraneoplastic syndrome

1. Small cell carcinoma of lung (most common) 2. Carcinoid

3. Medullary thyroid carcinoma. 4. Islet cell tumor of pancreas.

5. Ectopic corticotrophin releasing hormone (CRH)

 Morphology

o Pituitary gland: Crooke hyaline change or Crooke bodies: homogenous light basophilic intracytoplasmic material, composed of intermediate keratin filaments. The normal granular basophilic cytoplasm of corticotroph cells is lost due continuous negative feedback.

o Exogenous or ectopic cortisol: bilateral cortical atrophy in adrenals (atrophy of fasciculata & reticularis)

o Adrenal hyperplasia: diffuse thickening of the cortex, may show multiple & bilateral 0.5-2cm nodules (nodular hyperplasia). Combined adrenal weight 30-50 g

 Adrenocortical adenoma :

 Single, encapsulated, yellow mass, Weight ≤ 30g

 Micro: similar to normal zona fasciculate which contain vacuoles full of lipid.

 Can be non-functioning (called incidentalinoma) found incidentally.  If functioning, the other adrenal is atrophic

 Adrenocortical carcinoma

 Large, not capsulated, weight ≥ 200 g

 Micro: anaplastic cells, hemorrhage, necrosis.  Can be functioning or not.

 If functioning, the other adrenal is atrophic

 Mostly are Sporadic or syndromic as; Li-Fraumeni ‘mutation in p53 which tumor suppressor’ & Beckwith-Weidman.

 Metastasis to lymph nodes, lung, but NOT bone.  Clinical features:

- Insidious, chronic onset (except for small cell carcinoma) - Early: weight gain (central, moon face), hypertension. - Muscle atrophy

- Hyperglycemia (inhibit uptake of glucose)

- Hyperpigmentation (more obivious in cushing dis.) - Hirsutism.

- Mood disturbance (depression). - Menstrual abnormality.

B) The Zone Granulosa; Hyperaldosteronism :

Hypernatremia, hypokalemia, hypertension

 Primary hyperaldosteronism :

 Adenoma (80% of cases), Conn syndrome. characterized by low serum renin  Adenoma is solitary, encapsulated, <2 cm

 No suppression of ACTH (ACTH in normal level), second adrenal is not atrophic.

 Micro: Adenoma: lipid laden (resemble fasciculate rather than granulosa),

due to most patient using diuresis for hypertension without investigation because mostly it is idiopathic, leading to accumulation of the diuretics (spironolactone) in the adrenal.

 Hyperplasia 19% (over activation of CYP11B2 gene), also characterized by low serum renin

 Hyperplasia: bilateral, enlarge, nodular.  Carcinoma is rare, NO exogenous.

Q: What causing adrenal mass with normal ACTH level? A: conn syndrome OR non-functional adenoma.

 Secondary hyperaldosteronism

 Always associated with high renin in serum which caused by hypovolemia → Decreased renal perfusion (renal artery stenosis)

 Nephrotic syndrome, congestive heart failure, cirrhosis. Those diseases accumulate the fluid in the interstitial → hypovolemia

 Pregnancy (estrogen induced)

C) The Zone Reticularis; Adrenogenital syndromes :

 Adrenal androgens are under the influence of ACTH (in contrast to gonads)  Increased production, with virilization, is commonly seen in adrenocortical

neoplasms (especially carcinoma) because some of the increased cortisol will turn to androgens.

 CONGENITAL ADRENAL HYPERPLASIA :

 Autosomal Recessive; affect both sexes  CYP21B gene mutation

 21-hydroxylase enzyme deficiency (range from mild to total loss)  Low production of cortisol, High ACTH.

 Accumulation of cortisol precursors → Shift to androgens à virilization, ambiguous genitalia in females, weight loss, early puberty

 Adrenal insufficiency

 Types; Primary acute insufficiency, Primary chronic insufficiency & Secondary insufficiency.

 Clinical symptoms appear after 90% reduction in adrenal size.

 hyperkalemia, hyponatremia, hypotension, hypoglycemia, fatigue, nausea, vomiting, Weight loss.

1. Acute insufficiency; causes:

o Sudden withdrawal of long-term steroid therapy. o Acute (stress) on top of chronic insufficiency o Massive adrenal hemorrhage

o Waterhouse-Friderichsen syndrome : bilateral adrenal damage secondary to bacterial infection (Neisseria meningitidis, pseudomonas sepsis)

2. Chronic insufficiency; causes:

o Addison disease, Autoimmune adrenalitis (70%), AIDS, TB, Metastatic cancer (lung, breast)

o Characterized by high ACTH, skin hyperpigmentation.

3. Secondary insufficiency; causes:

o Low production of ACTH from pituitary, Any disease in hypothalamus pituitary axis

o Low ACTH, NO hyperpigmentation, other pituitary hormone(s) deficiency

 Pheochromocytoma :

 Tumor of chromaffin cells, adrenal medulla.  Synthesize and secrete Catecholamines  Refractory hypertension (very bad)

 10% familial (MEN syndrome), 10% bilateral, 10% extra-adrenal (paraganglioma), 10% malignant.

 Micro: zellballen pattern (small balls), finely granular cytoplasm positive for silver stain.

Mitosis, pleomorphism, polygonal and spindle cells, lymphatic and vascular permeation can be seen in benign lesion.

 Metastasis is the definite diagnosis for malignancy, Because the normal, benign, malignant can look the same.

Multiple Endocrine Neoplasia (MEN)

1) MEN type 1

 Autosomal Dominant.

 The patient born with single mutation, later in life, Inactivation of both alleles of MEN1 gene, located on 11q13 (tumor suppressor gene) then the symptom start.

 Multiple parathyroid hyperplasia (95%)

 Pancreas (40%), often functional (insulinoma, gastrinoma), fatal hypoglycemia, behave aggressively with metastasis

 Pituitary (30%), prolactinoma is most common

2) MEN type 2

 Activating mutation in RET proto-oncogene on 10q11.2  The type of mutation strongly affects the clinical severity

 Genetic testing for RET mutation if member of the family has mutation.  Prophylactic thyroidectomy should be done because 100% they will develop

medullary thyroid cancer which is aggressive. A. MEN type 2A

o Medullary thyroid carcinoma (100%), in the 1st _{two decades of life, C-cell}

hyperplasia

o Adrenal medulla: 50% develop Pheochromocytoma o Parathyroid: ⅓ develop hyperplasia

B. MEN type 2B

o Similar to MEN 2A, but no parathyroid hyperplasia o Develop ganglioneuroma of mucosal sites (GI) o Marfan-like features.