Pathology (Endocrine, parathyroid, adrenal)

Surgery

Autoimmune

• Autoimmune hypoparathyroidism is often associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency
• caused by mutations in the autoimmune regulator (AIRE) gene.
• The syndrome typically presents in childhood with the onset of candidiasis, followed several years later by hypoparathyroidism and then adrenal insufficiency during adolescence.

• Caused by gain-of-function mutations in the calcium-sensing receptor (CASR) gene
• Inappropriate CASR activity due to abnormal calcium sensing suppresses PTH, resulting in hypocalcemia and hypercalciuria.

Abnormal precursor of PTH or development of the glands

• Neuromuscular irritability, circumoral numbness or paresthesias (tingling) of the distal extremities and carpopedal spasm, to life-threatening laryngospasm and generalized seizures, Chvostek sign and Trousseau sign
• Mental status changes include emotional instability, anxiety to frank psychosis.  • Intracranial manifestations include calcifications of the basal ganglia, parkinsonian-like movement disorders, and increased intracranial pressure with resultant papilledema. The paradoxical association of hypocalcemia with calcifications may be because of an increase in phosphate levels, resulting in tissue deposits with locally produced calcium.   
• Ocular disease takes the form of calcification of the lens and cataract formation.  
• Cardiovascular manifestations include a conduction defect that produces a characteristic prolongation of the QT interval in the electrocardiogram.  
• Dental abnormalities occur when hypocalcemia is present during early development. These findings are highly characteristic of hypoparathyroidism and include dental hypoplasia, failure of eruption, defective enamel and root formation, and abraded carious teeth.

• Autosomal dominant disease with a loss-of-function mutation of the GNAS1 (alpha subunit of G protein) gene, leading to an inability to activate adenyl cyclase when PTH binds to its receptor.
• Maternal transmission of the mutation is required for expression of disease.
• Albright's hereditary osteodystrophy (AHO) that includes round facies, short stature, short fourth metacarpal bones, obesity, subcutaneous calcifications, and developmental delay
• PTH resistance of the renal tubule leads to hyperphosphatemia and hypocalcemia, and secondary hyperparathyroidism and hyperparathyroid bone disease (osteitis fibrosa).
• Show resistance to various other G-protein coupled hormones including thyroid-stimulating hormone, luteinizing hormone, follicular-stimulating hormone, and gonadotropin-releasing hormone as well as blunted response to beta-adrenergic agonists

If acquired from father, no hormone disturbance is present , but only symptoms of Albright's hereditary osteodystrophy.

Hyperparathyroidism (primary)/ malignancy

Adenoma/ Renal failure

• MEN1 (11q- tumor suppressor)--> loss of function/ also seen in sporadic
• MEN2a (RET, 10)--> gain of function
• Familial hypocalciuric hypercalcemia-->loss of function mutation in calcium-sensing receptor

MEN1 mutation, Cyclin D1 inversion

• 1. Almost always solitary
• 2. Is invested by a delicate capsule.
• 3. In contrast to primary hyperplasia, the glands outside the adenoma are usually normal in size or somewhat shrunken.
• 4. Uniform, polygonal chief cells with small, centrally placed nuclei
• 5. Mitotic figures are rare, but bizarre and pleomorphic nuclei which is not a criterion for malignancy.
• 6. In contrast to the normal parathyroid parenchyma, adipose tissue is inconspicuous.
• 

• There is frequently asymmetry with apparent sparing of one or two glands
• The most common pattern seen is chief cell hyperplasia
• Less commonly, the constituent cells contain abundant water-clear cells (“water-clear cell hyperplasia”).
• As in the case of adenomas, stromal fat is inconspicuous within the foci of hyperplasia.

• They are arrayed in nodular or trabecular patterns with a dense, fibrous capsule enclosing the mass.
• Invasion of surrounding tissues and metastasis are the only reliable criteria.

• Increased numbers of osteoclasts, which erode bone matrix and mobilize calcium salts, particularly in the metaphyses of long tubular bones.
• Increased osteoblastic activity and the formation of new bony trabeculae (widely spaced, delicate trabeculae reminiscent of those seen in osteoporosis.
• Thinning of cortex and increased amounts of fibrous tissue accompanied by foci of hemorrhage and cyst formation in marrow (osteitis fibrosa cystica).
• Aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris occasionally form masses that may be mistaken for neoplasms (brown tumors of hyperparathyroidism).

• Nephrocalcinosis, stone
• Metastatic calcification in stomach, lungs, myocardium, and blood vessels

• Malignancy
• Vit D toxicity
• Immobilization
• Thiazide
• Sarcoidosis (activation of 1-alpha hydroxylase)

• Bone disease and bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica.
• Nephrolithiasis (renal stones) in 20% of newly diagnosed patients, with attendant pain and obstructive uropathy. Chronic renal insufficiency and abnormalities in renal function lead to polyuria and secondary polydipsia.  
• Gastrointestinal disturbances, including constipation, nausea, peptic ulcers, pancreatitis, and gallstones.  
• Central nervous system alterations, including depression, lethargy, and eventually seizures.  
• Neuromuscular abnormalities, including weakness and fatigue.  
• Cardiac manifestations, including aortic or mitral valve calcifications (or both).
• The abnormalities most directly related to hyperparathyroidism are nephrolithiasis and bone disease, whereas those attributable to hypercalcemia include fatigue, weakness, and constipation. The pathogenesis of many of the other manifestations of the disorder remains poorly understood.

• 1. Gland Hyperplasia
• 2. Metastatic calcification may be seen in many tissues, including lungs, heart, stomach, and blood vessels.
• 3. OFC and brown tumor (less severe than primary)
• 4. The vascular calcification may result in significant ischemic damage to skin and other organs, a process sometimes referred to as calciphylaxis. 
• 5. Tertiary hyperparathyroidism

INTERNAL REDISTRIBUTION: Increased insulin secretion (due to increase in glycolysis), particularly during refeeding, Acute respiratory alkalosis (PFK activity and glycolysis increases), Hungry bone syndrome

DECREASED INTESTINAL ABSORPTION: Inadequate intake, Antacids containing aluminum or magnesium, Steatorrhea and chronic diarrhea

INCREASED URINARY EXCRETION: Primary and secondary hyperparathyroidism, Vitamin D deficiency or resistance, Primary renal phosphate wasting, Fanconi syndrome

• 1. Hypophosphatemia-induced changes in mineral metabolism include a decrease in distal tubular reabsorption of calcium and magnesium and increased bone resorption (rise in calcitriol), both resulting in hypercalciuria.
• Prolonged hypophosphatemia may lead to rickets and osteomalacia.
• 2. Decreased intracellular ATP levels may cause metabolic encephalopathy, impaired myocardial contractility, respiratory failure due to weakness of the diaphragm, a proximal myopathy, dysphagia and ileus.
• 3. Acute hypophosphatemia superimposed upon preexisting severe phosphate depletion may cause rhabdomyolysis (only alcoholics).
• 4. The hematologic effects of a hypophosphatemia-induced decrease in intracellular ATP levels include an increased predisposition to hemolysis, a decrease in both phagocytosis and granulocyte chemotaxis, and defective clot retraction and thrombocytopenia.

• 1. Cell lysis
• 2. Cell shift (DKA, lactic acidosis) +diminished glycolysis due to acidosis
• 3. RF
• 4. Increased tubular reabsorption of phosphate: Hypoparathyroidism, Acromegaly, Bisphosphonates, Vitamin D toxicity

• HYPOCALCEMIA WITH LOW PTH: (HYPOPARATHYROIDISM): Destruction of the parathyroid glands, Abnormal parathyroid gland development, Altered regulation of PTH (familial: activatin mutation in ca-sensing receptor or abnormal precursor of PTH)
• HYPOCALCEMIA WITH HIGH PTH: Vitamin D deficiency or resistance, Chronic kidney disease, PTH resistance (impaired PTH action), Extravascular deposition (Hyperphosphatemia- Osteoblastic metastases- Acute pancreatitis), Sepsis or severe illness
• DISORDERS OF MAGNESIUM METABOLISM (PTH reistance or decreased secretion in severe cases): cisplatin, alcohol, malabsroption
• DRUGS: Calcium chelators (citrate, foscarnet, Na EDTA) , Bisphosphonates (decreased osteoclastic activity) Denosumab (RANKL mAb--> inhibit osteoclast differentiation) Cinacalcet (decrease PTH secretion), Chemotherapy (cisplatin),Foscarnet (complex with ionized Ca), Fluoride poisoning
• Also Alkalosis--> increase binding to albumin

BONE RESORPTION: Primary hyperparathyroidism, Malignancy, Thyrotoxicosis, immobilization, hypervitaminosis A

CALCIUM ABSORPTION: Increased calcium intake (rare),  Chronic kidney disease, Milk alkali syndrome (due to CaCO3--> alkalosis, RF, and hypercalcemia), Hypervitaminosis D

Other: Lithium (decrease PTH sensitivity to Calcium), Thiazide diuretics, Pheochromocytoma (MEN), Adrenal insufficiency, Rhabdomyolysis and acute renal failure, Theophylline toxicity, Familial hypocalciuric hypercalcemia (like lithium)

• Overwhelming bacterial infection, classically Neisseria meningitidis septicemia but occasionally (Pseudomonas, pneumococci, H.I, or staphylococci)  
• Rapidly progressive hypotension leading to shock  
• DIC associated with widespread purpura
• Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage (DIC+LPS-induced vasculitis)
• Hemorrhage start in medulla near thin-walled sinusoids

• Bilateral hemorrhage (neonate with asphyxia due to normal deficiency of prothrombin, DIC, anticoagulation,and Waterhouse-Friderichsen Syndrome)
• Stress or crisis in chronic insufficiency
• Rapid withdrawal of GC

• 1. Autoimmune (MCC) autoAb to 17 alpha hydroxylase, or 21 hydroxylase
• 2. TB (also fungi coccidioides, histoplasmosis)
• 3. Metastases (lung, breast)
• 4. AIDS (CMV, MAI, KS)
• 5. Genetic (CAH, ALD)

• APS1 --> chronic mucocutaneous candidiasis and abnormalities of skin, dental enamel, and nails (ectodermal dystrophy), autoimmune adrenalitis, autoimmune hypoparathyroidism, idiopathic hypogonadism, pernicious anemia: AIRE (on 22) is expressed primarily in the thymus, and is important in self-tolerance.
• APS2--> starts in early adulthood and presents as a combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes. No mucocutaneous candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism.

• Primary autoimmune adrenalitis--> shrunken glands, residual cortical cells in a collapsed network of connective tissue, lymphoid infiltrate, medulla is otherwise preserved
• Tuberculous and fungal disease t--> granuloma
• Metastatic carcinoma--> the adrenals are enlarged
• Secondary--> Decreased size, normal ZG, or medulla

• PRIMARY--> Insidious onset.
• 1. The initial manifestations include progressive weakness and easy fatigability. 
• 2. GI --> anorexia, nausea, vomiting, weight loss, and diarrhea.
• 3. hyperpigmentation
• 4. Decreased mineralocorticoid --> hyperkalemia, hyponatremia, volume depletion, and hypotension.
• 5. Hypoglycemia --> impaired gluconeogenesis.
• 6. Stresses can precipitate an acute adrenal crisis, manifested by intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse. 
• 7. Eosinophilia, lymphocytosis, neutropenia

SECONDARY--> Low ACTH, No hyperpigmentation, no MC deficiency

Suppression of ACTH (secondary)

• 1. 21-OH--> reduced GC ±MC (DOC and aldosterone)/ increased androgens of adrenals/ increased 17OH progestrone
• 2. 11-OH--> reduced GC, increased DOC/ decreased aldosterone, increased adrenal androgens/ increased DOC and 11-deoxycortisole
• 3. 17-OH--> reduced GC, increased DOC/ decreased aldosterone/ decreased testis and adrenal androgens/ increased DOC and conrticosterone

4. 3-beta HSD--> reduced GC, MC, androgen in male, increased androgen (DHEA) in female/  increased DHEA

All increased ACTH

(1) salt-wasting (classic) adrenogenitalism (with MC deficiency) (2) simple virilizing adrenogenitalism (without MC deficiency), and (3) nonclassic adrenogenitalism (in puberty)

recombination with a neighboring pseudogene on chromosome 6p21 called CYP21A1 (a pseudogene is an inactive homologous gene created by ancestral duplication in a localized region of the genome)

Conversion of progesterone to 11-deoxycorticosterone (main cause of MC deficiency) or 17-OH progesterone to 11-deoxycortisole

Ambiguous genitalia (in male no genital manifestation)

• 1. Bilateral hyperplasia
• 2. The adrenal cortex is thickened and nodular, and on cut section the widened cortex appears brown, because of total depletion of all lipid
• 3. Hyperplasia of corticotroph

High levels of intra-adrenal glucocorticoids are required to facilitate medullary catecholamine (epinephrine and norepinephrine) synthesis. In patients with severe salt-wasting 21-hydroxylase deficiency, a combination of low cortisol levels and developmental defects of the medulla (adrenomedullary dysplasia) profoundly affects catecholamine secretion, further predisposing these individuals to hypotension and circulatory collapse.

• 1. AR
• 2. Ambiguous genitalia in female infants, and hyperpigemented scrotum in males
• 3. early puberty and adult short stature
• 4. Infertility in most female
• 5. Most male are fertile, a few not because of adrenal rests in testis +leydig cell dysfunction, and seminiferous abnormality causing oligospermia
• 6. 21-hydroxylase deficiency compromises both the development and subsequent functioning of the adrenomedullary system

Exogenous

ACTH-secreting pituitary microadenoma (Cushing disease)

Pulmonary small-cell carcinoma, bronchial carcinoid, MTC

CRH-secreting tumor

Adrenal adenoma (less common carcinoma)

ACTH secreting tumor (primary hyperplasia is rare)

• The condition is ACTH independent, but not entirely “autonomous.”
• Cortisol production is regulated by non-ACTH circulating hormones, as a result of ectopic overexpression of their corresponding receptors in the adrenocortical cells (GIP, LH, ADH, and serotonin)
• A subset of macronodular hyperplasia arises in the setting of McCune-Albright syndrome, characterized by germline activating mutations in GNAS, which encodes a stimulatory Gsα.

Pituitary (regardless of cause) and Adrenal

Crooke hyaline change: the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary becomes homogeneous and paler due to accumulation of intermediate keratin filaments in the cytoplasm.

• 1. Exogenous GC (bilateral cortical atrophy due to reduced ACTH/ ZG is normal)
• 2. ACTH elevation (Diffuse hyperplasia with variable size nodules and lipid-rich vacoulated and lipid-poor eosinophilic cells)
• 3. Macronodular hyperplasia (adrenals are almost entirely replaced by prominent nodules. Unlike diffuse hyperplasia, the areas between the macroscopic nodules also demonstrate evidence of microscopic nodularity). 
• 4. Micronodular hyperplasia is composed of 1- to 3-mm darkly pigmented (lipofuscin) (brown to black) micronodules, with atrophic intervening areas. 
• 5. Adenomas are yellow tumors surrounded by capsules and normal cells of ZF
• 6. Carcinomas are larger, without capsule, anaplastic
• In both adenoma and carcinoma the remainder of gland is atrophic

Obesity

• 1. Early stages --> hypertension and weight gain
• 2. Truncal obesity, moon facies, and buffalo hump.
• 3. Selective atrophy of fast-twitch (type 2) myofibers, resulting in decreased muscle mass and proximal limb weakness.
• 4. Enhanced gluconeogenesis and inhibition of the uptake of glucose by cells--> DM
• 5. The catabolic effects cause loss of collagen and resorption of bones. Consequently the skin is thin, fragile, and easily bruised; wound healing is poor; and cutaneous striae are particularly common in the abdominal area
• 6. Osteoporosis, renal stones
• 7. Increased risk for infections
• 8. Several mental disturbances
• 9. Hirsutism and menstrual abnormalities, decreased libido

(1) the 24-hour urine free-cortisol concentration, which is increased, and (2) loss of normal diurnal pattern of cortisol secretion

• 1. Cushing disease--> elevated ACTH which cannot be suppressed by LDDM. Hence, there is no reduction in urinary excretion of 17-hydroxycorticosteroids but is suppressed by HDDM 
• 2.   Ectopic ACTH secretion -->elevated level of ACTH is not suppressed by HDDM 
• 3. Adrenal tumor--> low ACTH

Bilateral idiopathic hyperaldosteronism (bilateral nodular hyperplasia)

• Bilateral idiopathic hyperaldosteronism
• Adrenocortical neoplasm, (mc adenoma)
• Glucocorticoid-remediable hyperaldosteronism

• It is caused by a chimeric gene resulting from fusion between the 11β -hydroxylase and the aldosterone synthase genes. Production of hybrid steroids in addition to both cortisol and aldosterone.
• The activation of aldosterone secretion is under the influence of ACTH and hence is suppressible by exogenous administration of dexamethasone.

Decreased PRA in primary, increased PRA in secondary

• Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)  
• Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome)  
• Pregnancy (due to estrogen-induced increases in plasma renin substrate)

• Well-circumscribed
• Buried within the gland
• Resemble ZF (NOT ZG)
• Eosinophilic, laminated cytoplasmic inclusions, (spironolactone bodies) after treatment with spironolactone
• No atrophy of the remained gland (unlike Cushing syndrome)

• Cell resemble ZG
• Diffuse
• Wedge-shaped

• HTN (mc) due to increase in CO and ECF (DBP)--> diastolic HF, LVH
• Weakness (hypokalemia)
• Tetany (metabolic alkalosis)
• Endothelial dysfunction by decreasing G6PD levels, which, in turn, reduces endothelial nitric oxide synthesis and causes oxidative stress.

• Screen by PRA
• if decreased--> Aldosterone suppression test

Adenomas and carcinomas are about equally common in adults; in children, carcinomas predominate

Li-Fraumeni syndrome (p53), and Beckwith-Wiedemann syndrome, an imprinting disorder (IGF-2)

• Functional adenomas are most commonly associated with hyperaldosteronism and Cushing syndrome, whereas a virilizing neoplasm is more likely to be a carcinoma
• Carcinomas are more likely to be functioning than adenoma

• More likely to be slient
• Well-circumscribed <2.5
• Yellow nodular
• Atrophy is present if adenoma is functional
• Some degree of atypia but rare mitosis

• Clinically functional (especially androgen)
• Large, invasive, necrotic, hemorrhagic, cystic changes
• Invade veins, LN, and viscera (bone is rare)
• Less common than metastasis (mc --> from lung)

Non-functioning adenoma

(1) branchiomeric, (2) intravagal, and (3) aorticosympathetic. The branchiomeric and intravagal paraganglia associated with the parasympathetic system are located close to the major arteries and cranial nerves of the head and neck and include the carotid bodies. The aorticosympathetic chain is found in association with segmental ganglia of the sympathetic system and therefore is distributed mainly alongside of the abdominal aorta. The organs of Zuckerkandl, close to the aortic bifurcation, belong to this group.

10% bilateral (more in familial), 10% malignant (more in familial and extra-adrenal), 10% extra-adrenal, 10% not associated with HTN

• 1) medulla and Zuckerkandl has PNMT --> produce both EPI and NE
• 2) other places do not have PNMT--> only produce NE
• 3) may also produce other hormones such as ACTH

• MEN2a and 2b (RET)
• VHL, Succinate dehydrogenase mutations (increased HIF-1alpha)
• NF1
• SDHB1 associated with paraganglioma and highest malignancy rates

• Well demarcated
• Richly vascularized fibrous trabeculae within the tumor produce a lobular pattern.
• Larger lesions tend to be hemorrhagic, necrotic, and cystic.
• Addition of potassium dichromate turns the tumor a dark brown color due to oxidation of stored catecholamines.
• Cells, clustered with the sustentacular cells into small nests or alveoli (zellballen) by a rich vascular network
• The cytoplasm has a finely granular appearance
• The nuclei are usually round to ovoid, with a stippled “salt and pepper” chromatin that is characteristic of neuroendocrine tumors.
• Electron microscopy reveals variable numbers of membrane-bound, electron-dense secretory granules.
• Chief cells positive for Chromogranin and synaptophysin
• Sustentacular cells positive for S-100, a calcium-binding protein expressed by a variety of mesenchymal cell types.
• The only reliable marker of malignancy is metastasis
• 

Nothing (only metastasis)

• HTN (90%)
• 2/3 paroxysmal (half with associated symptoms tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension) may be precipitated by stress or positional change
• Others sustained chronic HTN
• orthostatic hypotension due to depleted IV volume

24-hour urine for metanephrine

Headache, palpitation, sweating

spontaneous or therapy-induced differentiation of primitive neuroblasts into mature elements, spontaneous tumor regression, and a wide range of clinical behavior and prognosis

neuroblastoma

Neuroblastoma

Germline mutations in the anaplastic lymphoma kinase (ALK) gene

• Adrenal medulla (40%)
• Paravertebral region of the abdomen (25%)
• Posterior mediastinum (15%)

Postganglionic sympathetic neurons (ganglia)

Small nodules of neuroblastic cells than mostly regress

• Small, primitive-appearing cells with dark nuclei, scant cytoplasm, and poorly defined cell borders.
• Mitotic activity, nuclear breakdown (“karyorrhexis”), and pleomorphism may be prominent.
• Faintly eosinophilic fibrillary material (neuropil) that corresponds to neuritic processes of the primitive neuroblasts. Homer-Wright pseudorosettes -->tumor cells are concentrically arranged about a central space filled with neuropil
• Positive neuron-specific enolase 
• Ultrastructural demonstration of small, membrane-bound, cytoplasmic catecholamine-containing secretory granules (contain characteristic central dense cores surrounded by a peripheral halo (dense core granules).
• 

• Larger cells having more abundant cytoplasm, large vesicular nuclei, and a prominent nucleolus, representing ganglion (ganglioneuroblastoma).
• Even better differentiated lesions contain many more large cells resembling mature ganglion cells with few if any residual neuroblasts (ganglioneuroma)
• Maturation of neuroblasts into ganglion cells is usually accompanied by the appearance of Schwann cells.
• Presence of schwannian stroma is associated with a favorable outcome

• Age <18 month --> better
• Stage 1,2,4S(<1 year+liver, BM, or skin metastasis)--> better

Amplification of the N-MYC oncogene (particularly in those with other criteria of good prognosis)

• 1. Stage 1,2,4S
• 2. Age<18 m (spontaneous regression)
• 3. Hyperdiploidy (versus hypodiploidy)
• 4. Negative N-MYC
• 5. Evidence of schwannian stroma and gangliocytic differentiation
• 6. Low Mitosis-karyorrhexis index
• 7. TRKA + , TRKB negative
• 8. 1p, 11q del negative

large abdominal masses, fever, and possibly weight loss (older --> metastasis)

• Periorbital metastasis + proptosis
• Widespread metastasis
• Multiple skin blue nodules in neonate
• Opsoclonus myoclonus syndrome
• Mass effect (ganglioneuroma only with mass effect)

Elevated urine and blood levels of HVA and VMA