Download Pathology Ch24 - Endocrine System - pp1073-1137

Pathology Ch24 - Endocrine System - pp1073-1137
Pituitary Gland
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Anterior lobe (adenohypophysis)
o PIT-1 expression > somatotrophs (GH), mammosomatotrophs (GH + PRL), lactotrophs (PRL)
o SF-1 and GATA-2 expression > gonadotrophs (FSH + LH)
o Remaining > corticotrophs (ACTH), thyrotrophs (TSH)
Posterior lobe (neurohypophysis)
o Glial cells (pituicytes)
o Axon terminals (extending from hypothalamus through pituitary stalk) > oxytocin + ADH/vasopressin
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Clinical Manifestations of Pituitary Disease
o Hyperpituitarism:
 From excess secretion of trophic hormones
 Causes: pituitary adenoma, hormone secretion from non-pituitary tumors, hypothalamic disorders
o Hypopituitarism:
 From deficiency of trophic hormones
 Causes: destructive processes (ischemia, surgery/radiation, inflammation, nonfunctional pit. adenoma)
o Local mass effects:
 Radiographic abnormalities of sella turcica (sellar expansion, bony erosion, disruption of diaphragm sella)
 Expanding pituitary lesions often compress optic chiasm > visual field abnormalities
 Can produce symptoms of elevated intracranial pressure > headache, nausea, vomiting
 Acute hemorrhage ("pituitary apoplexy") > rapid enlargement of lesion > can cause sudden death
o Diseases of posterior pituitary cause clinical symptoms associated w/ inc./dec. ADH
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Pituitary Adenomas and Hyperpituitarism
o Most common cause of hyperpituitarism is an adenoma in the anterior lobe
o Can be functional (associated w/ hormone excess) or nonfunctioning (w/o clinical symptoms of hormone excess)
 Functional: classified by hormones that are produced by neoplastic cells (some can secrete 2)
 Lactotroph (PRL) > galactorrhea and amenorrhea, sexual dysfunction, infertility
 Somatotroph (GH) >
o Densely granualted adenoma > gigantism (children)
o Sparsely granulated adenoma > acromegaly (adults)
 Mammosomatotroph (PRL, GH) > combined features of GH and PRL excess
 Corticotroph (ACTH, POMC-derivatives)
o Densely granulated > Cushing syndrome
o Sparsely granulated > Nelson syndrome
 Thyrotroph (TSH) > hyperthyroidism
 Gonadotroph (FSH, LH) > hypogonadism, mass effects, hypopituitarism
 Nonfunctional: can encroach/destroy pituitary parenchyma if large enough
 Microadenomas (<1cm diameter); macroadenomas (>1cm diameter)
 Pituitary incidentaloma: vast majority of lesions, clinically silent microadenomas
o Genetic mutations associated w/ pituitary adenomas
 Gain of function:
 GNAS: G-protein subunit Gsα always activated > upregulation of cAMP ***
o GH adenomas
o 40% of somatotroph cell adenomas bear GNAS mutation
 Protein kinase A, regulatory subunit 1 (PRKAR1A): loss of PKA regulation > elevated cAMP activity
o GH and prolactin adenomas
 Cyclin D1: over expression promotes G1-S transition > aggressive adenomas
 HRAS: loss of oncogenic pathway regulation > activate mutation > pituitary carcinoma
 Loss of function:
 MEN1: loss of menin tumor suppression function > GH, PRL, ACTH adenomas
 CDKN1B (p27/KIP1): loss of p27 negative regulator of cell cycle > ACTH adenomas
 Aryl hydrocarbon receptor interacting protein (AIP): pituitary adenoma predisposition > GH aden.
 Retinoblastoma (RB): loss of RB negative regulator of cell cycle > aggressive adenomas
o Morphology
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 Typically soft and well-circumscribed
 Distinguished from parenchyma by cellular monomorphism and absence of reticulin network
 Larger lesions extend superiorly through diaphragm > compress optic chiasm
 Invasive adenomas = 30% not grossly encapsulated > infiltrated neighboring tissues (sinuses, dura, brain)
 Atypical adenomas = elevated mitotic behavior and p53 expression > TP53 mutation. More aggressive.
Clinical features
 Excessive secretion of pituitary hormones
 Local mass effect > visual field abnormalities + elevated intracranial pressure (+ hypopituitarism)
 Acute hemorrhage into an adenoma associated w/ pituitary apoplexy
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Lactotroph Adenoma (PRL)
 Most frequent types of hyperfunctioning pituitary adenoma (30% of clinical cases)
 Diagnosed more readily in women between 20-40yo due to amenorrhea
 Men and older women manifest more subtle symptoms > tumors grow very large before detection
 Morphology
 Sparsely granulated lactotroph adenomas = juxtanuclear localization of PIT-1
 Densely granulated lactotroph adenomas = diffuse cytoplasmic PIT-1 expression
 Propensity to undergo dystrophic calcification > "pituitary stone"
 Prolactinemia (increased PRL) > amenorrhea, galactorrhea, loss of libido, and infertility
 Can also be caused by lactotroph hyperplasia due to loss of dopamine inhibition (damage to stalk
or dopaminergic neurons)
 Any mass in the suprasellar compartment may disturb normal inhibitory influence
 Other causes: renal failure and hypothyroidism
 Treatment: surgery, or bromocriptine (dopamine receptor agonist)
o
Somatotroph Adenoma (GH)
 Second most common type of functioning pituitary adenoma
 Persistently high levels of GH stimulate hepatic secretion of insulin-like growth factor 1 (IGF-1)
 In children, before epiphyses close > gigantism (increase in body size, long arms/legs)
 In adults, after epiphyses close > acromegaly (bone density increase in spine/hips,
enlarged/protruding jaw, broadening of lower face, enlarged hands/feet, sausage-like fingers)
 Can also be associated w/ gonadal dysfunction, diabetes mellitus, muscle weakness,
hypertension, arthritis, congestive heart failure, inc. risk of GI cancers
 Morphology
 Densely granulated = monomorphic acidophilic cells, strong cytoplasmic GH reactivity
 Sparsely granulated = chromophobe cells w/ nuclear/cytologic pleomorphism, weak GH staining
 Mammosomatotroph adenomas = bihormonal (secrete GH and prolactin)
 Diagnosed by elevated serum GH and IGF-1 levels + failure to suppress GH in response to oral glucose load
 Treatment: surgery, somatostatin analogues, or GH receptor antagonists
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Corticotroph Adenoma (ACTH)
 Leads to adrenal hypersecretion of cortisol > hypercortisolism (Cushing syndrome)
 Morphology
 Densely granulated = basophillic
 Sparsely granulated = chromophobic
 Stain positively w/ PAS due to presence of carbs in POMC and ACTH precursor molecules
 Cushing disease = excessive ACTH
 Nelson syndrome = develop destructive pituitary adenomas after removal of adrenal glands (loss of
inhibitory effect of adrenal corticosteroids), but hypercortisolism doesn't develop
o
Other Anterior Pituitary Adenomas
 Gonadotroph adenomas (LH- and FSH-producing)
 Difficult to recognize b/c secretions usually do not cause clinical manifestation
 Found when grown sufficiently to cause impaired vision, headaches, diplopia, or pit. apoplexy
 Hormone deficiencies can be found (most commonly LH deficiency) > decreased energy and
libido in men, and amenorrhea in premenopausal women
 Thyrotroph adenomas (TSH-producing): 1% of adenomas, rare cause of hyperthyroidism
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Nonfunctioning (silent aka null-cell) pituitary adenomas: 25-30% of all pituitary tumors, mass effect >
compress anterior pituitary > hypopituitarism
Pituitary carcinomas: 1% of adenomas, characterized by craniospinal or systemic metastases, most are
functional > prolactin and ACTH produced
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Hypopituitarism
o Hypofunctioning @ >75% parenchyma loss
o Disease of hypothalamus or pituitary > decreased secretion of pituitary hormones
 Tumors and other mass lesions (pituitary adenomas, benign tumors within the sella, cysts, malignancies)
 Traumatic brain injury and subarachnoid hemorrhage
 Pituitary surgery or radiation of pituitary adenomas
 Pituitary apoplexy = sudden hemorrhage into the pituitary gland, common w/ pituitary adenoma
 Sudden onset excruciating headache, diplopia, and hypopituitarism
 Possible CV collapse, loss of consciousness, and death
 Ischemic necrosis of the pituitary and Sheehan syndrome (postpartum necrosis)
 Pituitary doubles in size during pregnancy, w/o any increase in vascularization
 Any further loss of blood flow can cause hypoxia of the anterior pituitary > necrosis
 Posterior pituitary has separate blood supply, and is less susceptible to ischemia
 Can also occur w/ DIC, sickle cell anemia, inc. intracranial pressure, traumatic injury, and shock
 Rathke cleft cyst: accumulate proteinaceous fluid > expand > compromise normal gland
 Empty sella syndrome:
 Primary: defect in the diaphragma sella > arachnoid mater and CSF herniates into sella
o Occurs in obese women w/ multiple pregnancies
o Present w/ visual field defects, and endocrine anomalies (hyperprolactinemia)
 Secondary: mass enlarges the sella > surgically removed or undergoes infarction > loss of pit. fxn
 Hypothalamic lesions: can also diminish ADH > diabetes insipidus
 Inflammatory disorders and infections: sarcoidosis or tuberculous meningitis can invade hypothalamus
 Genetic defects: ex. mutation of PIT-1 > deficiencies of GH/prolactin/TSH
o Clinical manifestations:
 GH deficiency > children can develop growth failure (pituitary dwarfism)
 Gonadotropins (LH/FSH) > amenorrhea/infertility, decreased libido/impotence/pubic or axillary hair loss
 TSH/ACTH deficiency > hypothyroidism and hypoadrenalism, respectively
 PRL deficiency > failure of postpartum lactation
 MSH (POMC derivative) deficiency > pallor
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Posterior Pituitary Syndromes
o Diabetes insipidus = ADH deficiency > low water resorption > polyuria, increased serum osmolality and [sodium]
 Central: lack of ADH secretion; Nephrogenic: lack of ADH response at kidneys
 Caused by head trauma, tumors, inflammatory disorders of hypothalamus/pituitary, surgical complication
o Syndrome of inappropriate ADH (SIADH) secretion = excess ADH > excess water resorption > hyponatremia
 Mostly caused by secretion of ectopic ADH by malignant neoplasms, drugs, or CNS disorders
 Result in hyponatremia > neurologic dysfunction
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Hypothalamic Suprasellar Tumors
o Neoplasms may induce hypo/hyperfunction of anterior pituitary, diabetes insipidus, or combination of these
o Most common = gliomas and craniopharyngiomas (arising from Rathke pouch)
o Pts present w/ headaches and visual disturbances
o Children can present w/ growth retardation due to pituitary hypofunction and GH deficiency
o Morphology
 Craniopharyngiomas = 3-4cm, commonly cystic, often encroach on the optic chiasm + cranial nn.
 Adamantinomatous = most often in children, demonstrate calcification
 Papillary = most often in adults, rarely show calcification
Thyroid Gland
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Hypothalamic factors > TSH released by anterior pituitary > thyroid G protein coupled receptors > inc. cAMP > secrete
Thyroid follicular epithelial cells convert thyroglobulin into thyroxine (T4) and a bit of triiodothyronin (T3)
T4/T3 released into circulation > carried via thyroxine-binding globulin and transthyretin
T4 deiodinated > T3 > 10x more potent effect on nuclear thyroid hormone receptors (TR) > gene expression on
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Stimulates carb and lipid catabolism and protein synthesis > inc. basal metabolic rate + brain development of fetus/neonate
Function can be inhibited by goitrogen agents > suppress T3/T4 synthesis > leads to inc. TSH > thyroid hyperplasia
Propylthiouracil inhibits oxidation of iodide > blocks production of hormones & peripheral deiodination
Parafollicular cells (C cells) > calcitonin > promote absorption of Ca+ by skeletal system & inhibits resorption by osteoclasts
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Hyperthyroidism
o Thyrotoxicosis = hypermetabolic sate caused by excess free T3/T4
 Most commonly due to hyperthyroidism
 Also can be due to thyroiditis or extrathyroidal source of T3/T4
o Primary hyperthyroidism = Diffuse hyperplasia (Graves), hyperfunctioning multinodular goiter or adenoma, iodineinduced hyperthyroidism, neonatal thyrotoxicosis associated w/ maternal Graves disease
o Secondary hyperthyroidism = TSH-secreting pituitary tumor
o Clinical course
 Increase in basal metabolic rate > warm skin, heat intolerance, weight loss despite inc. appetite
 Cardiac manifestations > inc. cardiac output, tachycardia, palpitations, cardiomegaly, left ventricular
dysfunction, thyrotoxic/hyperthyroid cardiomyopathy (low output heart failure)
 Overactivity of sympathetic nervous system > tremors, hyperactivity, emotinal lability, anxiety, inability to
concentrate, and insomnia, proximal muscle weakness (thyroid myopathy), diarrhea, malabsorption
 Ocular changes > wide/staring gaze and lid lag. Proptosis in Graves disease.
 Skeletal system > inc. porosity of bone, atrophy of skeletal muscle, lymphoid hyperplasia (Graves)
 Thyroid storm > underlying Graves disease + acute catecholamine increase > febrile, tachycardia
 Apathetics hyperthyroidism > older people w/o compensatory mechanisms
o Diagnosed:
 Decreased serum TSH w/ increased T3/T4
 Administer TRH > determine whether it's due to pituitary or thyroid
o Rx: β-blocker for sympathetic symptoms, thionamide to block hormone synthesis, iodine solution to block release
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Hypothyroidism
o Hypothyroidism: structural or functional derangement that interferes w/ the production of thyroid hormone
 Fairly common: clinical manifestations in 0.3% of population, subclinical in 4% of population
 Prevalence increases w/ age, and is 10x more common in women than men
 Can result in defect anywhere alone hypothalamic-pituitary-thyroid axis
 Primary (congenital, autoimmune, or iatrogenic) and secondary (pituitary or hypothalamic failure)
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Congenital Hypothyroidism: most often the result of endemic iodine deficiency in the diet
 Inborn errors of thyroid metabolism (dyshormonogenetic goiter) in any of the multiple synthesis steps
 (1) Iodide transport into thyrocytes, (2) organification of iodine in thyroglobulin, and (3) iodotyrosine
coupling
 Rare instances of thyroid agenesis (absence of parenchyma) or hypoplasia (greatly reduced in size)
o
Autoimmune Hypothyroidism: most common cause of hypothyroidism in iodine-sufficient areas
 Vast majority caused by Hashimoto thyroiditis
 Circulating autoantibodies (antimicrosomal, antithyroid peroxidase, antithyroglobulin) found in the
disorder
 Thyroid typically enlarged (goiter)
o
Iatrogenic Hypothyroidism: caused by either surgical or radiation-induced ablation
 Large resection to treat hyperthyroidism can lead to hypothyroidism
 Radioiodine or exogenous irradiation can also destroy it
 Drugs given to decrease thyroid secretion (methimazole/propylthiouracil) can also cause acquired
hypothyroidism
 Can also be caused by drugs that treat other conditions (lithium, aminosalicylic acid)
 Secondary (central) hypothyroidism due to damage to the pituitary or hypothalamus (TSH or TRH
deficiencies)
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Cretinism: hypothyroidism that develops in infancy or early childhood
 Results in impaired skeletal and CNS development > severe mental retardation, short stature, coarse facial
features, protruding tongue, and umbilical hernia
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Severity of mental retardation related to time at which thyroid deficiency occurs in utero
 Early maternal deficiency = most severe
 Late deficiency, after fetus develops its own thyroid = less severe
Myxedema: hypothyroidism that develops in older children or adults
 Older children show intermediate symptoms between cretinism and adult hypothyroidism
 Adult condition appears slowly and make take years before clinically manifesting
 Myxedema marked by slowing of physical and mental activity (initial signs may mimic depression)
 Decreased sympathetic activity > constipation and decreased sweating, decreased cardiac output
 Promotes atherogenic profile > increase in total cholesterol and LDL levels
 Accumulation of matrix substances (glycosaminoglycans, hyaluronic acid) in skin, subcutaneous tissue,
and visceral sites > nonpitting edema, enlargement of tongue, and deepening of voice
 Laboratory evaluation should be conducted for patients w/ unexplained increase in body weight or
hypercholesterolemia > measurement of serum TSH levels is the most sensitive screening test
 Elevated in primary hypothyroidism as a result of loss of feedback inhibition of TRH/TSH
 Not elevated in person w/ primary hypothalamic or pituitary disease
Thyroiditis
o Hashimoto Thyroiditis
 Autoimmune disease that destroys the thyroid gland w/ gradual and progressive thyroid failure
 Most prevalent between 45-65 years, most common in women
 Pathogenesis: caused by breakdown in self-tolerance to thyroid autoantigens
 Presence of autoantibodies against thyroglobulin and thyroid peroxidase in majority of patients
 Increased susceptibility linked to polymorphisms in immune regulation genes: CTLA4 and PTPN22
 Induction of autoimmunity accompanied by progressive depletion of thyroid epithelial cells via:
o CD8+ cytotoxic T cell-mediated cell death
o Cytokine-mediated cell death (due to activation of CD4+ T cells > γ-IFN cytokines)
o Binding of antithyroid antibodies > antibody-dependent cell-mediated cytotoxicity
 Morphology:
 Thyroid often diffusely enlarged
 Extensive infiltration of the parenchyma by mononuclear inflammatory infiltrate
 Thyroid follicles are atrophic, lined by epithelial Hurthle cells
 Interstitial CT is increased and may be abundant
 Unlike Reidel thyroiditis, the fibrosis does not extend beyond the capsule of the gland
 Clinical Course:
 Most often noticed a painless symmetric goiter that develops gradually in middle-aged women
 Initial onset may display large release of T3/T4 due to follicle cell breakdown, and subsequent
low TSH
 As hypothyroidism supervenes, T4/T3 levels fall and TSH becomes elevated
 Individuals w/ Hashimoto have increased risk of developing other autoimmune diseases, along
w/ lymphomas within the thyroid gland
o
Subacute Lymphocytic (Painless) Thyroiditis
 Noticed as mild hyperthyroidism, goiter enlargement, or both
 Most often in middle-aged adults, more common in women
 Variant of autoimmune thyroitidtis > have circulating antithyroid peroxidase antibodies
 Morphology:
 Thyroid appears grossly normal w/ maybe mild enlargement
 Microscope examination reveals lymphocytic infiltration within parenchyma and collapse of
follicles
 Fibrosis and Hurthle cell metaplasia are NOT prominent
 Clinical Course:
 Some patients transition from hyperthyroidism to hypothyroidism before recovery
o
Granulomatous (de Quervain) Thyroititis
 Most common between 40-50 years, affects women more
 Pathogenesis:
 Triggered by viral infection (many patients have history of recent upper respiratory infection)
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Exposure to a viral or thyroid antigen secondary to virus-induced host tissue damage > stimulates
cytotoxic T lymphocytes > damage thyroid follicular cells
 Immune response is virus-initiated, and NOT self-perpetuating > process is limited
Morphology:
 Gland may be unilaterally or bilaterally enlarged and firm
 Histological changes are patchy
 Multinucleated giant cells enclose naked pools or fragments of colloid > "granulomatous"
 Later stages associated w/ chronic inflammatory infiltrate and fibrosis
Clinical Course:
 Most common cause of thyroid pain
 Inflammation and hyperthyroidism are transient > last 2-6 weeks > normal thyroid fxn in 6-8
weeks
 Patients show high T4/T3 and low TSH
Reidel Thyroiditis (RARE)
 Extensive fibrosis involving the thyroid and contiguous neck structures
 Manifestation of a systemic autoimmune IgG4-related disease
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Graves Disease
o Most common cause of endogenous hyperthyroidism
o (1) Hyperthyroidism w/ diffuse enlargement, (2) infiltrative opthalmopathy > exophthalmos, (3) infiltrative
dermopathy (pretibial myxedema)
o Peaks between 20-40 years, women affected 10x as often as men
o Pathogenesis: autoimmune production of autoantibodies against multiple thyroid proteins (esp. TSH receptors)
 Antibodies can either stimulate or block TSH receptors
 Thyroid stimulating immunoglobulin (TSI) seen in 90% of patients > binds/activates TSH receptors
 Also linked to genetic polymorphisms in CTLA4 and PTPN22, and the HLA-DR3 allele
 Glycosaminoglycan deposition and lymphoid infiltrations are responsible for opthalmopathy and
dermopathy
o Morphology:
 Gland symmetrically enlarged due to diffuse hypertrophy and hyperplasia of follicular epithelial cells
 Lymphoid infiltrates present throughout the interstitium
 Can lead to lymphoid hyperplasia (esp. thymus), heart hypertrophy, edemantous tissues of the orbit, and
thickening of the dermis
o Clinical Course:
 Degree of thyrotoxicosis varies from case to case
 Diffuse enlargement of the thyroid present in all cases
 Extraocular muscles are often weak > exophthalmos may persist or progress despite successful treatment
 Patients are at risk for other autoimmune disease
 Lab findings shot elevated T3/T4 and depressed TSH levels
 Treated w/ β-blockers to address sympathetic symptoms and thinamides/radioiodine/thyroidectomy
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Diffuse and Multinodular Goiters
o Enlargement of the thyroid (goiter) caused by impaired synthesis of thyroid hormone
o Impaired thyroid hormone synthesis > compensatory serum TSH rise > hypertrophy/hyperplasia of thyroid cells
o Most often result of dietary iodine deficiency
o
Diffuse Nontoxic (Simple) Goiter
 Enlargement of the entire gland w/o producing nodularity
 Follicles filled w/ colloid > "colloid goiter"
 Endemic goiter
 Where soil, water, and food supply contain low levels of iodine
o Common in mountainous areas (Andres and Himalayas)
 Certain foods can act as goiterogens (cabbage, cauliflower, Brussels sprouts, turnips, cassava)
o Cassava especially for some Native populations
 Sporadic goiter
 Females more likely, peaking at puberty or in young adult life
 Results from hereditary enzymatic defects or ingestion of goiterogens
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Morphology
 Hyperplastic phase = thyroid diffusely and symmetrically enlarged
 Colloid involution phase = increase in dietary iodine or dec. demand for thyroid hormone >
stimulated follicular epithelium involutes > enlarged, colloid-rich gland
Clinical Course
 Vast majority have normally functioning thyroid gland
 Clinical manifestations related to mass effect
Multinodular Goiter
 Recurrent episodes of hyperplasia/involution > irregular enlargement of the thyroid
 Produce the most extreme thyroid enlargements (commonly mistaken for neoplasms)
 Arise due to variations among follicular cells in response to external stimuli (ex. trophic hormones)
 May lead to rupture of follicles and vessels > hemorrhages, scarring, calficiation
 Morphology
 Multilobated, asymmetrical enlarged glands
 May involve only one lobe > lateral pressure on midline structures (trachea/esophagus)
 Intrathoracic aka plunging goiter = grows behind the sternum/clavicles
 Clinical Course
 Dominant clinical feature of mass effects
 May cause airway obstruction, dysphagia, and compression of large vessels in neck/thorax
 Most pts have normal thyroid fxn or have subclinical hyperthyroidism
 Plummer syndrome = minority of pts w/ autonomous nodule produces hyperthyroidism (toxic
multinodular goiter), but not accompanied by opthalmopathy or dermopathy of Graves
 Low chance of malignancy, but especially if goiters show sudden change in size or symptoms
Neoplasms of the Thyroid
o Solitary nodules > more likely to be neoplastic
o Nodules in younger pts > more likely to be neoplastic
o Nodules in males > more likely to be neoplastic
o Hx of radiation to head and neck > inc. incidence of thyroid malignancy
o Functional nodules that take up radioactive iodine (hot nodules) > much more likely to be benign
o
Adenomas
 Typically discrete, solitary masses, derived from follicular epithelium (>> "follicular adenomas")
 Vast majority are nonfunctional, but "toxic adenomas" can cause thyrotoxicosis independent of TSH
 Pathogenesis
 Toxic adenomas show somatic mutations of TSH receptor signaling pathway
o Most often gene encoding TSH receptor (TSHR) or α-subunit of Gs (GNAS)
o Leads to symptoms of hyperthyroidism
o Produces "hot" nodule on imaging
 Minority of nonfunctioning adenomas have mutations of RAS or PIK3CA (like carcinomas)
 Morphology
 Solitary, spherical, encapsulated, well-demarcated lesion (unlike multinodular goiters)
 Areas of hemorrhage, fibrosis, calcification, and cystic change (like multinodular goiters)
 Hallmark = intact, well-formed capsule encircling tumor (unlike follicular carcinomas)
 Clinical Features
 Many present as unilateral painless mass
 Larger masses may produce local symptoms (ex. dysphagia)
 Nonfunctioning adenomas take less radioactive iodine vs normal parenchyma > "cold" nodules
 Need to evaluate capsular integrity for definitive diagnosis (requires biopsy)
 Do not recur or metastasize > excellent prognosis
o
Carcinomas
 Derived from thyroid follicular epithelum (except medullary carcinomas)
 Vast majority are well-differentiated lesions
 Early and middle adult = mostly women
 Childhood and late life = equal distribution M:F
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Pathogenesis
 Genetic Factors
o Alterations in growth factor receptor signaling pathways > follicular carcinomas
o Gain-of-function mutation in RAS/MAPK/PI3K and growth factor receptor
o Papillary carcinoma
 RET gene > segment translocation or inversion > RET/PTC gene
 Encodes receptor tyrosine kinase (normally not expressed)
 More common w/ backdrop of radiation exposure
 NTRK1 > constitutively active NTRK1 fusion proteins
 BRAF gene > gain-of-function intermediate of MAP kinase pathway signaling
o Follicular carcinoma
 Mutations that activate RAS or PIK3CA (PI3K/AKT signaling pathway)
 Loss of function mutations of PTEN tumor suppressor
o Anaplastic (undifferentiated) carcinoma
 Contain modifications found in papillary and follicular carcinoma
 Triggered by inactivation of TP53 or activating β-catenin
o Medullary thyroid carcinoma
 Associated w/ germline RET mutations
 RET/PTC translocations NOT found
 Environmental Factors
o Ionizing radiation, particularly during first 2 decades of life
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Papillary Carcinoma (>85%)
 Most often between 25-50yo w/ history of ionizing radiation exposure
 Morphology
o Branching papillae
o Nuclei contain finely dispersed chromatin > optically clear/empty appearance > groundglass or Ophan Annie eye nuclei
o Nuclei invaginations > intranuclear inclusions or intranuclear grooves
o Concentrically calcified structures (psammoma bodies)
o Foci of lymphatic invasion by tumor often present
o Follicular variant = characteristic nuclear features and follicular architecture, w/ high
propensity for angioninvasion and lower incidence of lymph node metastases
o Tall-cell variant = tall columnar cells lining the papillary structures, aggressive
o Diffuse sclerosing variant = in younger adults and children, extensive diffuse fibrosis
throughout gland
o Papillary microcarcinoma = <1cm in size
 Clinical Course
o Present as asymptomatic thyroid nodules, or mass in cervical lymph nodes
o Advanced disease = hoarseness, dysphagia, cough, or dyspnea
o Hematogenous metastases most common to lungs
o Excellent prognosis = 95% 10-year survival
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Follicular Carcinoma (5-15%)
 Most frequent in areas w/ dietary iodine deficiency
 More common in women and older pts (40-60yo)
 Morphology
o Larger lesions may penetrate the capsule > infiltrate the neck
o Central fibrosis and foci of calcification sometimes present
o Occasionally dominated by cells w/ abundant granular, eosinophilic cytoplasm (Hurthle
cell or oncocytic variant of follicular carcinoma)
o Nuclei optically clear w/ nuclear grooves
o Lymphatic spread is uncommon (unlike papillary carcinoma)
 Clinical Course
o Slowly enlarging painless nodules
o Regional lymph nodes rarely involved
o Hematogenous dissemination is common > bone, lungs, liver
o Widely invasive follicular carcinoma has poor 10 year prognosis
o
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Anaplastic (Undifferentiated) Carcinoma (<5%)
 Most common in pts >65yo w/ history of well-differentiated carcinoma in 1/2 of pts
 Aggressive, 100% mortality
 Morphology
o Highly anaplastic cells w/ variable morphology
 Large pleomorphic giant cells
 Spindle cells w/ sarcomatous appearance
 Mixed giant and spindle cells
 Clinical Course
o Present as rapidly enlarging bulky neck mass
o Already spread beyond thyroid capsule into neck and metastasized to lungs
o Symptoms of dyspnea, dysphagia, dysphagia, hoarseness, and cough
o No effective therapies > fatal within a year
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Medullary Carcinoma (5%)
 Derived from parafollicular cells (C cells)
 Secrete calcitonin > useful for diagnosis and post-op follow-up
 Some can also secrete serotonin, ACTH, and VIP
 Early in life = associated w/ MEN types 2A and 2B
 Adulthood (40-50yo) = sporadic or associated familial medullary carcinomas
 Morphology
o Amyloid deposits (from calcitonin polypeptides) present in stroma
o C-cell hyerplasia and bilaterality/multicentricity common in familial cases
 Clinical Course
o Sporadic cases = mass in neck, w/ dysphagia or hoarseness
 Paraneoplastic syndrome (diarrhea from VIP, Cushings from ACTH)
 Hypocalcemia not present despite elevated levels of calcitonin
o Familial = thyroid symptoms or endocrine neoplasms in other organs
o MEN-2B = more agggressive w/ more metastsizing
Congenital Anomalies
 Thyroglossal duct cyst
 Sinus tract persists as vestige of tubular development of thyroid gland
 Parts of this tube obliterate > small segments that can form cysts
 Manifest at any age, and may not become evident until adult life
 Cysts accumulate liquid > spherical masses in midline of neck anterior to trachea
 Rarely give rise to cancers
Parathyroid Glands
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
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
Functions to regulate calcium homeostasis
Controlled by levels of free (ionized) calcium in blood
o Decreased calcium in blood > synthesis/secretion of PTH
 Increase renal tubular resorption of calcium
 Increase conversion of vitamin D to active dihydroxy form in kidneys
 Increase urinary phosphate excretion
 Augments GI calcium absorption
o Elevated levels of free calcium > inhibit further PTH secretion
Chief cells = contain secretory granules w/ parathyroid hormone
Oxyphil cells = glycogen granules, but sparse/absent secretory granules
Hyperparathyroidism
o Primary hyperparathyroidism
 Autonomous overproduction of PTH, resulting from adenoma or hyperplasia of parathyroid tissue
 Adenoma = 85-95%
o Cyclin D1 gene inversions > overexpression of cyclin D1 (regulator of cell cycle)
o MEN1 mutations (tumor suppressor gene)
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



 Hyperplasia = 5-10%
 Carcinoma = 1%
Usually in adults (>50yo), and more common in women (4:1)
80% diagnosed via incidental hypercalcemia finding in serum electrolyte panel
Morphology
 Adenomas > surrounding cells are normal or even small (to compensate for PTH overproduction)
 Hyperplasia > frequently all 4 glands are involved, but can be asymmetric
 Carcinomas > enlarge one parathyroid gland, diagnosed by metastasis
 Skeletal abnormalities = osteoporosis, brown tumors, osteitis fibrosa cystica (von Recklinghausen
disease of bone)
 Urinary abnormalities = formation of urinary tract stones (nephrolithiasis) and calcification of
renal interstitium and tubule (nephrocalcinosis)
Clinical Course
 Asymptomatic hyperparathyroidism
o Hypercalcemia or hypophosphatemia incidentally found
 Symptomatic primary hyperparathyroidism
o Bone disease and bone pain (osteoporosis or osteitis fibrosa cystica)
o Nephrolithiasis, chronic renal insufficiency
o GI disturbances (constipation, nausea, peptic ulcers, pancreatitis, gallstones)
o CNS alterations (depression, lethargy, seizures)
o Neuromuscular abnormalities (weakness, fatigue)
o Cardiac manifestations (aortic and/or mitral valve calcificatation)
o
Secondary hyperparathyroidism
 Compensatory hypersecretion of PTH due to prolonged hypocalcemia (common in chronic renal failure)
 Renal failure most common, but can be caused by low dietary intake, steatorrhea, and vit D deficiency
 Chronic renal failure > dec. phosphate excretion > hyperphosphatemia > depress serum Ca++ levels
 Morphology
 Hyperplastic parathyroid glands, not necessarily symmetric
 Increased number of chief cells
 Metastatic calcification may be seen in many tissues (lungs, heart, stomach, vasculature)
 Clinical Course
 Clinical features usually dominated by renal failure
 Skeletal abnormalities tend to be milder vs primary hyperparathyroidism
 Calciphylaxis = vascular calcification > ischemic damage to skin and other organs
 Rx: dietary vitamin D supplement + phosphate binders
o
Tertiary hyperparathyroidism
 Persistent hypersecretion of PTH even after hypocalcemia corrected (ex. after renal transplant)
 Rx: parathyroidectomy
Hypoparathyroidism
o Almost always an inadvertent consequence of surgery =
 Inadvertent removal during thyroidectomy
 Excision thinking they're lymph nodes
 Removal of too much tissue in treatment of primary hyperparathyroidism
o Autoimmune hypoparathyroidism = mutation in autoimmune regulator (AIRE) > autoimmune polyendocrine
syndrome type 1 (APS1). Presents in childhood w/onset of candidiasis > hypoparathyroidism > adrenal insufficiency
o Autosomal-dominant hypoparathyroidism = gain-of-fxn in calcium-sensing receptor (CASR) gene
o Familial isolated hypoparathyroidism = mutation in gene encoding PTH precursor peptide, or loss-of-fxn in glial
cells missing-2 (GCM2) essential for parathyroid development
o Congenital absence = can occur w/ thymic aplasia and CV defects, or w/ DiGeorge syndrome (thymic defects)
o Clinical Features
 Hypocalcemia > tetany > Chvostek sign (tape on facial nerves > contraction) and Trousseau sign (carpal
spasms via occlusion of circulation to forearm/hand w/ blood pressure cuff for a few minutes)
 Mental status changes = emotional instability, anxiety/depression, confused, hallucinations, psychosis
 Intracranial manifestations = calcification of basal ganglia, inc. intracranial pressure, parkinsonian-like
movements disorders
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o
Ocular disease = calcification of lens and cataract formation
CV manifestations = conduction defect > prolonged QT interval
Dental abnormalities = hypocalcemia present during early development > dental hypoplasia, failure of
eruption, defective enamel and root formation, abraded carious teeth
Pseudohypoparathyroidism
 Occurs due to end-organ resistance to PTH actions
 PTH levels are normal or elevated, hypocalcemia, hyperphosphatemia
 One form includes resistance to TSH and FSH/LH, as well as PTH (all G-protein coupled receptors)
 TSH resistance generally mild
 LH/FSH resistances > hypergonadotropic hypogonadism in females
The Endocrine Pancreas

Islets of Langerhans contain 4 major and 2 minor cell types
o β = secrete insulin > reduces blood glucose levels
o α = secrete glucagon > stimulates glycogenolysis in liver to increase blood glucose
o δ = secrete somatostatin > suppresses insulin and glucagon release
o PP = secrete pancreatic polypeptide > stimulates secetion of gastric and intestinal enzymes, inhibits motility
o D1 = secrete vasoactive intestinal polypeptide (VIP) > induces glycogenolysis and hyperglycemia; and stimulates GI
fluid secretion > secondary diarrhea
o Enterochromaffin cells = secrete serotonin; often source of pancreatic tumors

Diabetes Mellitus
 Group of metabolic disorders sharing the common features of hyperglycemia
o Results from defect in insulin secretion, insulin action, or both
o Associated w/ secondary damage to kidneys, eyes, nerves, and blood vessels

Diagnosis
o Blood glucose normally maintained at 70-120 mg/dL
o Diagnostic criteria for diabetes (need to be repeated/confirmed on separate day):
 Fasting plasma glucose >126 mg/dL
 Random plasma glucose >200 mg/dL
 2-hour plasma glucose >200 mg/dL (oral glucose tolerance test [OGTT] = 75 g dose)
 And, glycated hemoglobin (HbA1C) >6.5%
o Diagnostic criteria for "prediabetes":
 Fasting plasma glucose 100-125 mg/dL
 2-hour plasma glucose 140-199 mg/dL (OGTT = 75 g)
 And/or, glycated hemoglobin (HbA1C) 5.7-6.4%

Classification
o Type I diabetes: autoimmune disease of pancreatic β cell destruction (5-10% of all cases)
 Immune-mediated or idiopathic
o Type II diabetes: insulin resistance and inadequate secretory response (relative insulin deficiency) (90-95%)
 Genetic defects of β-cell function: maturity-onset diabetes of the young (MODY), Hepatocyte nuclear
factor, neonatal diabetes, maternally inherited diabetes and deafness (MIDD)
 Genetic defects in insulin action: type A insulin resistance, lipoatrophic diabetes
 Exocrine pancreatic defects: chronic pancreatitis, neoplasia, cystic fibrosis, hemochromatosis
 Endocrinopathies: acromegaly, Cushing syndrome, hyperthyroidism, glucagonoma
 Infections: cytomegalovirus, coxsackie B virus, congenital rubella
 Drugs: glucocorticoids, thyroid hormone, interferon-α, protease inhibitors, β-blockers, thiazies
 Genetic syndromes associated w/ diabetes: down, klinefelter, turner, prader-willi
 Gestational diabetes mellitus
o Type I vs Type II
 Clinical:
 Onset: usually childhood or adolescence vs. usually adult
 Normal weight or weight loss vs. majority (80%) are obese
 Progressive decrease in insulin levels vs increase > normal > moderate decrease
 Circulating islet autoantibodies vs no islet autoantibodies
 Diabetic ketoacidosis in absence of insulin vs nonketotic hyperosmolar coma more common

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Genetics:
 Type I = MHC class II genes, CTLA4, PTPN22, VNTR polymorphisms
 Type II = no HLA linkage, link to diabetogenic and obesity-related genes (TCF7L2, PPARG,
FTO)
Pathogenesis:
 Type I = dysfunction in T cell selection and regulation > breakdown in self-tolerance
 Type II = insulin resistance in peripheral tissue, failure of compensation by β-cells, multiple
obesity-associated factors (nonesterified fatty acids, inflammatory mediators,
adipocytokines)
Pathology:
 Type I = insulitis (inflammatory infiltrate of T cells and macrophages), β-cell depletion, islet
atrophy
 Type II = no insulitis, amyloid deposition in islets, mild β-cell depletion

Glucose Homeostasis
o Tightly regulated by (1) glucose production in liver, (2) glucose uptake/utilization in peripheral tissue - esp.
skeletal muscle, (3) actions of insulin and counter-regulatory hormones (glucagon) on glucose uptake and
metabolism
 Fasting = high glucagon activity
 After meal = high insulin activity, low glucagon activity
o Regulation of Insulin Release
 Synthesized as precursor > cleaved to mature hormone in Golgi > insulin + C-peptide > stored in
vesicles
 Most important stimulus for insulin synthesis and release is glucose
 Glucose uptake into β cells via GLUT-2 > metabolized to generate ATP
 ATP inhibits activity of ATP-sensitive K+ channel > membrane depolarization > Ca++ influx
 Increased intracellular Ca++ >> insulin secretion from storage vesicles
 Incretins: promote insulin secretion after eating
 K cells in proximal small bowel >> Glucose-dependent insulinotropic polypeptide (GIP)
 L cells in distal ileum and colon >> Glucagon-like peptide-1 (GLP-1)
 Degraded in circulation by dipeptidyl peptidases (DPPs), especially DPP-4
 Incretin effect significantly blunted in type II diabetes (possible therapy via receptor
agonists)
o Insulin Action and Insulin Signaling Pathways
 Insulin is most potent anabolic hormone
 Adipose tissue: inc. glucose uptake, inc. lipogenesis, dec. lipolysis
 Striated muscle: inc. glucose uptake, inc. glycogen synthesis, inc. AA uptake/protein
synthesis
 Liver: inc. glycogen synthesis, inc. lipogenesis, dec. gluconeogenesis
 Mitogenic functions: initiation of DNA synthesis in certain cells and stimulation of their
growth
 Insulin receptor: tetrametic protein 2xα (transmembrane) + 2xβ subunits (cytosolic)
 Cytosolic domain possesses tyrosine kinase activity > phosphorylate insulin receptor
substrates (IRS1-IRS4 and GAB1) > activate downstream signaling PI3K and MAP kinase
pathways
 PI3K > AKT >> or CBL >> GLUT-4 vesicle moves to membrane

Pathogenesis of Type I Diabetes Mellitus
o Islet destruction is caused primarily by immune effector cells reacting against endogenous β-cell antigens
 Without insulin > ketoacidosis and coma
o Genetic Susceptibility
 Most important locus is the HLA(-DR3/4) gene cluster on chromosome 6p21 > 50% of type I diabetes
 Insulin w/ variable number of tandem repeats (VNTRs) in promoter region
 CTLA4 and PTPN22 linked to autoimmune thyroiditis
o Environmental Factors
 Viral infections (via molecular mimicry of islet cells)
 Viral infections can also be protective against type I diabetes ???
o Mechanisms of β Cell Destruction
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

Abnormality in type I diabetes is failure of self-tolerance in T cells specific for islet antigens
Initial activation of these nodes thought to occur in peripancreatic lymph nodes
Not clear if autoantibodies cause injury or are merely produced as consequence of islet injury

Pathogenesis of Type II Diabetes Mellitus
o Involves interplay of genetic and environmental factors and proinflammatory state - no autoimmune basis
o Genetic Factors
 5-10x higher risk if it runs in the family
 Gene loci associated are related to insulin secretion
o Environmental Factors
 Most important risk factor is obesity, particularly central or visceral obesity
 Even moderate weight loss can reduce insulin resistance and improve glucose tolerance
o Metabolic Defects in Diabetes
 Insulin resistance: failure of target tissue to respond normally to insulin
 Predates development of hyperglycemia, accompanied by β-cell hyperfunction
 Results in:
o Failure to inhibit endogenous glucose production in liver > high fasting glucose
o Failure of glucose uptake and glycogen synthesis > high post-meal glucose
o Failure to inhibit lipoprotein lipase in adipose > excess free fatty acids > amp.
resistance
 Effects of obesity:
o Free fatty acids = overwhelm intracellular fatty acid oxidation pathways >
accumulate toxic DAG intermediates; complete w/ glucose > feedback inhibit
glycolytic enzymes
o Adipokines = proteins secreted by adipose tissue into circulation, some w/ glucose
effect
o inflammation = cytokines released in response to excess nutrients (FFA/glucose) >
insulin resistance and β-cell dysfunction
 β-cell dysfunction: requirement for development of overt diabetes
 Initially inc. in fxn as compensatory mechanism > exhaust their capacity to adapt long term
 Caused by:
o Excess FFA compromise β-cell fxn via "lipotoxicity"
o "Glucotoxicity" from chronic hyperglycemia
o Abnormal incretin effect > reduced GIP and GLP-1 secretion
o "Burnout" via amyloid deposition within islets
o Genetic factors

Monogenic Forms of Diabetes
o Genetic Defects in β-Cell Function
 Largest subgroup of patients = maturity-onset diabetes of the young (MODY)
 Germline loss-of-function mutation in one of six genes
 Glucokinase (GCK) most common > rate limiting step in oxidative glucose metabolism
 Mutations of ATP-sensitive K+-channels
 Mutations in mitochondrial DNA (impede ATP synthesis)
 Mutations of insulin gene itself
o Genetic Defects that Impair Tissue Response to Insulin
 Rare insulin receptor mutations:
 Receptor synthesis
 Insulin binding
 Receptor tyrosine kinase activity
 Pt present w/ velvety hyperpigmentation of skin ("acanthosis nigricans"), abnormal fat deposition in
the liver (hepatic steatosis), hypertriglyceridemia, diabetes, and insulin resistance

Diabetes and Pregnancy
o Pregestational = diabetic woman becomes pregnant > increased risk of stillbirth and congenital malformations
o Gestational diabetes = develop diabetes during pregnancy > excessive birth weight in newborn (macrosomia)

Clinical Features of Diabetes
o
o
Type I Diabetes: can occur at any age, kicks in after "honeymoon period" of endogenous insulin secretion
Type II Diabetes: typically older than 40 and obese, increasingly younger, often diagnosed by routine blood
testing
o
The Classic Triad of Diabetes
 Onset of type I diabetes marked by polyuria, polydipsia, and polyphagia
 Severe diabetes manifests as diabetic ketoacidosis
 Deficiency of insulin results in catabolic state > weight loss and muscle weakness
o
Acute Metabolic Complications of Diabetes
 Diabetic ketoacidosis: occurs in type I and II, but more severe in type I
 Common precipitating factor = failure to take insulin, or other stress inducers
 Many factors associated w/ epinephrine (blocks residual insulin action > stimulates
glucagon)
 Activation of ketogenic machinery
 Insulin deficiency > lipoprotein lipase > increase FFA > oxidation in the liver > ketone bodies
 Urinary excretion of ketones compromised by dehydration > metabolic ketoacidosis
o Fatigue, nausea, vomiting, severe abdominal fain, fruity odor, deep/labored
breathing (Kussmaul breathing) >> eventual depression of cerebral consciousness >
coma
 Reversed by administration of insulin, correction of metabolic acidosis, and treatment of
underlying factors (ex. infection)
 Hyperosmolar hyperosmotic syndrome (HHS): more common in type II diabetes
 Severe dehydration > sustained osmotic diuresis
 Symptoms of ketoacidosis not present > delayed presentation to hospital > severe
hyperglycemia
 Hyperglycemia seen in range of 600-1200 mg/dL
 Most common acute metabolic complication of either diabetes = HYPOglycemia
 Usually results of missing a meal, excessive physical exertion, or excess insulin
administration
 Symptoms: dizziness, confusion, sweating, palpations, tachycardia >> loss of consciousness
 Reversed by oral/IV glucose intake > prevent onset of permanent neurological damage
o
Chronic Complications of Diabetes
 Morbidity associated w/ longstanding diabetes due to damage induced in large and medium-sized
muscular arteries (diabetic macrovascular disease) and in small vessels (diabetic microvascular
disease)
 Macrovascular disease > accelerated atherosclerosis > increased MI, stroke, lower extremity ischemia
 Microvascular disease > retina, kidneys, peripheral nerve > retinopathy, nephropathy, neuropathy
 Pathogenesis of Chronic Complications
 Persistent hyperglycemia (glucotoxicity) responsible for long term complications
 Assessment of glycemia control based on percentage of glycated hemoglobin (Hb A1C)
o Formed by addition of glucose moieties to hemoglobin in red cells
o Provides measure of glycemic control over lifespan of RBC (120 days)
o Recommended to be maintained below 7% in diabetic patients
 Increased glucose flux through various intracellular metabolic pathways is thought to
generate harmful precursors that contribute to end organ damage
 Formation of Advanced Glycation End Products (AGEs)
 Reactions between intracellular glucose-derived dicarbonyl precursors w/ amino groups of
both intracellular and extracellular proteins
 Natural rate of AGE formation is greatly accelerated by hyperglycemia
 AGEs bind to specific receptor (RAGE) expressed on inflammatory cells (macrophages and T
cells), endothelium, and vascular SM
 AGE-RAGE signaling axis detrimental effects:
o Release of cytokines and growth factors (TGFβ) (deposition of excess basement
membrane material) and vascular endothelial growth factor (VEGF) (retinopathy)
o Generation of reactive oxygen species (ROS) in endothelial cells
o Increased procoagulant activity on endothelial cells and macrophages
o Enhanced proliferation of vascular smooth muscle cells and synthesis of ECM
Antagonists of RAGE = therapeutic strategy in diabetes
AGE can also cross-like ECM proteins > decreases protein removal while enhancing
deposition
Activation of Protein Kinase C
 Hyperglycemia stimulates de novo synthesis of DAG from glycolytic intermediates > excess
PKC
 PCK activation > production of VEGF, TGFβ, and PAI-1 (plasminogen activator inhibitor)
 Effects contribute to diabetic microangiopathy
Oxidative Stress and Disturbances in Polyol Pathways
 Excess intracellular glucose metabolized by aldose reductase to sorbitol > fructose (using
NADPH)
 NADPH is required by glutathione reductase to regenerate reduced glutathione
 Lack of glutathione (GSH) > lack of antioxidant mechanism in the cell
Hexosamine Pathways and Generation of Fructose-6-Phosphate
 Increased intracellular levels of F-6-P > generations of excess proteoglycans
 Glycosylation changes accompanied by abnormal expression of TGPβ and PAI-1
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o
Morphology and Clinical Features of Chronic Complications of Diabetes
 Related to the late systemic complications of diabetes
 Pancreas
 Reduction in number and size of islets (most often in type I diabetes)
 Leukocyte infiltrates in the islets ("insulitis")
 Subtle reduction in islet cell mass (type II diabetes)
 Amyloid deposition within islets (type II diabetes)
 Increase in number and size of islets (hyperplasia in response to maternal hyperglycemia)
 Diabetic Macrovascular Disease
 Accelerated atherosclerosis (aorta and large/medium sized arteries)
o MI is most common cause of death in diabetes
 Gangrene of the lower extremities (advanced vascular disease)
 Hyaline arteriolosclerosis = hyaline thickening in walls of arterioles > narrows lumen
 Diabetic Microangiopathy
 Diffuse thickening of basement membranes
 Diabetic capillaries are more leaky to plasma proteins
 Microangiopathy underlies development of diabetic nephropathy, retinopathy, and
neuropathy
 Diabetic Nephropathy
 Renal failure is second only to MI as cause of death
 Three lesions: (1) glomerular, (2) renal vascular, (3) pyelonephritis
 Capillary basement membrane thickening: occurs progressively beginning 2-5 years after
onset
 Diffuse mesangial sclerosis: increase in mesangial matrix > deterioration of renal function
 Nodular glomerulosclerosis (aka intercapillary glomerulosclerosis aka Kimmelstiel-Wilson
disease): progresses to enlarged nodules that may compress and engulf capillaries. Nodules
frequently accompanied by accumulateions of hyaline in capillary loops (fibrin caps) or
adherent to Bowman capsules (capsular drops). Results in kidney ischemia > tubular atrophy
> interstitial fibrosis
 Renal atherosclerosis and arterioslcerosis: macrovascular
 Pyelonephritis: acute or chronic inflammation of the kidney (necrotizing papillitis esp.
prevalent)
 Diabetic Ocular Complications
 Hyperglycemia leads to acquired opacification of the lens (cataract)
 Also associated w/ intraocular pressure (glaucoma) and resulting damage to optic nerve
 Most profound histopathologic changes are seen in the retina
 Diabetic Neuropathy
 Depends on duration of the disease
 Up to 50% have peripheral neuropathy clinically (up to 80% if disease >15 years)
o

Clinical Manifestations of Chronic Diabetes
 Long-term effects of diabetes (appearing 15-20 years after onset) responsible for morbidity/mortality
 Macrovascular complications (MI, renal vascular insufficiency, cerebrovascular accidents)
 Hypertension
 Dyslipidemia (increases triglycerides and LDL, decreases HDL)
 Elevated PAI-1 > inhibitor of fibrinolysis > atherosclerotic plaques
 Diabetic nephropathy is leading cause of end-stage renal disease in US
 Early manifestations = microalbuminuria = excess albumin in urine 30-300 mg/day
 Without intervention > overt nephropathy w/ macroalbuminuria = >300mg/day
 75% type I and 20% type II will develop end-stage renal disease requiring dialysis or
transplant
 Visual impairment (sometimes blindness)
 Neovascularization attributable to hypoxia-induced VEGF overexpression in the retina
 Also increased propensity for glaucoma and cataract formation
 Diabetic neuropathy
 Can afflict the CNS, peripheral sensorimotor nerves, and ANS
 Most common = distal symmetric polyneuropathy of lower extremities affecting
motor/sensory
 Autonomic neuropathy > bowel/bladder/ED disturbances
 Diabetic mononeuropathy > sudden footdrop, wristdrop, or isolated CN palsies
 Enhanced susceptibility to infections of the skin and to tuberculosis, pneumonia, and pyelonophritis
 Infections cause death in 5% of diabetics
 Diabetic neuropathy pt can have an infection in a toe become long succession of
complications
 Due to decreased neutrophil functions, and impaired cytokine production by macrophages
 Vascular compromise reduces delivery of circulating cells and molecules required for
defense
Pancreatic Neuroendocrine Tumors (PanNETs)
o Rare in comparison to exocrine pancreas tumors
o Malignant = metastaes, vascular invasion, and local infiltration
o 90% insulin producing tumors are benign
o 60-90% of other functioning or nonfunctioning neoplasms are malignant
o Recurrent somatic alterations
 MEN1 mutation > familial MEN syndrome type 1
 Loss-of-function PTEN and TSC tumor suppressors
 Inactivating mutations in alpha-thalassemia/mental retardation syndome, X-linked (ATRX) and deathdomain associated protein (DAXX)
o
Hyperinsulinism (Insulinoma)
 β-cell tumors (insulinomas) = most common
 Produce sufficient insulin > hypoglycemia (<50 mg/dL of serum)
 Clinical manifestations: confusion, stupor, loss of consciousness (due to fasting or exercise)
 Rx: feeding or parenteral administration of glucose
 Morphology
 Generally benign, solitary tumors
 Carcinomas diagnosed by local invasion and metastases
 Characteristic deposition of amyloid
 Clinical Features
 80% of cases are clinically mild/asymptomatic
 Lab findings: high levels of insulin and high insulin:glucose ratio
 Rx: surgical removal of tumor
 Notice that hyperinsulemia may be related to other conditions: abnormal insulin sensitivity,
diffuse liver disease, inherited glycogenoss, ectopic production of insulin by retroperitoneal
fibromas and fibrosarcomas, and hypoglycemia induced by insulin self-injection
o
Zollinger-Ellison Syndrome (Gastrinomas)
 Hypersecretion of gastrin by gastrin-producing tumors (gastrinomas)
 Likely sources are endocrine cells of gut or pancreas
 Association of pancreatic islet cell lesions, hypersecretion of gastric acid, and severe peptic ulcerations
 Morphology
 >50% are locally invasive and have already metastasized by time of diagnosis
 25% of pts have gastrinomas in conjunction w/ other endocrine tumors (MEN-1 syndrome)
 Duodenal and gastric ulcers are often multiple, and don't respond to therapy
 Ulcers may occur in unusual locations (ex. jejunum) > suspect Zollinger-Ellison syndrome
 Clinical Features
 >50% of pts have diarrhea
 Rx: HK-ATPase inhibitors (control HCl release) and excision of neoplasm
 Hepatic metastases > shortened life expectancy
o
Other Rare Pancreatic Endocrine Neoplasms
 α-cell tumors (glucagonomas) = inc. serum glucagon + mild diabetes mellitus, necrolytic migratory
erythema (characteristic skin rash), and anemia. Most common in peri/postmenopausal women.
 δ-cell tumors (somatostatinomas) = diabetes mellitus, cholelithiasis, steathorrhea, and hypochlorhydria
 VIPoma = watery diarrhea, hypokalemia, achlorhydria, or WDHA syndrome
 Pancreatic carcinoid tumors = produce serotonin
 Multihormonal tumors = produce ACTH, MSH, ADH, serotonin, and norepinephrine
Adrenal Glands

Adrenal Cortex
o Zona glomerulosa (beneath capsule) = mineralocorticoids (aldosterone) SALT
o Zona fasciculata = glucocorticoids (cortisol) SUGAR
o Zona reticularis (abuts medulla) = sex steroids (estrogen and androgens) SEX
o
Adrenocortical Hyperfunction (Hyperadrenalism)
 Hypercortisolism (Cushing Syndrome)
 Exogenous = administration of glucocorticoids ("iatrogenic" Cushing syndrome)

Endogenous ACTH-dependent
o ACTH-secreting pituitary adenomas (70%)
 Pituitary form = Cushing's disease
 Affects women 4x more than men, and occurs most in young adults
 Mostly caused by ACTH-producing pituitary microadenoma
o Secretion of ectopic ACTH by nonpituitary tumors (10%)
 Mostly caused by ACTH-producing small-cell carcinoma of the lung

Endogenous ACTH-independent
o Elevated serum cortisol, but low ACTH
o Adrenal adenomas (10%) = women affected 4x more than men
o Adrenal carcinomas (5%) = more marked hypercortisolism vs adenomas
o Macronodular hyperplasia = cortisol secretion regulated by non-ACTH hormones
o Primary pigmented nodular adrenal disease = mutations in PRKARIA and PDE11
o McCune-Albright syndrome = mutations that activate GNAS > cAMP

Morphology
o Crooke hyaline change in pituitary
o Dependings on cause, adrenals show:
 Cortical atrophy = exogenous glucocorticoids
 Diffuse hyperplasia = ACTH-dependent
 Macronodular or micronodular hyperplasia = ACTH-independent
 Adenoma or carcinoma = ACTH-independent
Clinical Course
o Early stages = HTN and weight gain
o Develop characteristic truncal obesity, moon facies, and buffalo hump

o
o
o
o
o
o
o
o

Primary Hyperaldosteronism
 Most commonly manifests as blood pressure elevation
o Bilateral idiopathic hyperaldosteronism (IHA) (60%)
 Nodular hyperplasia of adrenal glands
 May be linked to KCNJ5 (potassium channel) mutation
 Less severe HTN than adrenal neoplasms
o Adrenocortical neoplasm (35%)
 Most commonly adenomas = Conn syndrome
 More common in women (2:1) in middle life
 Some linked to KCNJ5 mutation
o Glucocorticoid-remediable hyperaldosteronism
 Mutation in CYP11B2 (aldosterone synthase) > placed under control of ACTHresponsive CYP11B1 promoter
 Suppressible by dexamethasone
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

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Atrophy of fast-twitch myofibers > decreased muscle mass + proximal limb weakness
Catabolic effects > loss of collagen and resorption of bone > thin skin + easily bruised +
cutaneous striae in abdominal area + osteoporosis
Glucocorticoids suppress immune system > increased infections
Mental disturbances = mood swings, depression, psychosis,
Hirsutism, menstrual abnormalities
Pituitary Cushing syndrome =
 ACTH not suppressed w/ oral dexamethasone > corticosteroids in urine
 IV dexamethasone suppresses ACTH > decreased corticosteroids in urine
Ectopic ACTH = completely insensitive to low/high dose dexamethasone
Adrenal tumor = ACTH levels low (feedback inhibition), no response to dexamethasone
Secondary hyperaldosteronism
o Renal hypoperfusion (arteriolar nephrosclerosis, renal artery stenosis)
o Arterial hypovolemia and edema (CHF, cirrhosis, nephrotic syndrome)
o Pregnancy (estrogen-induced inc. in plasma renin)
Morphology
o Adenomas =
 Buried inside gland and don't always show up on imaging
 Characteristic spironolactone bodies after Rx w/ anti-HTN spironolactone
o Bilateral idopathic hyperplasia = wedge-shaped, subtle enlargement
Clinical Course
o Hypertension due to salt/water retention
o Long-term = CV compromise (L ventricular hypertrophy + reduced diastolic volume)
o Sometimes hypokalemia > weakness, paresthesias, visual disturbances, tetany
o Diagnosed by elevated plasma aldosterone relative to renin activity
o Confirmed by aldosterone suppression test
Adrenogenital Syndromes
 Disorders of sexual differentiation (ex. virilization or feminization)
 Cortex secretes dehydroepiandrosterone and adnrostenedione > converted to testosterone
 Can be due to ACTH excess, adrenocortical neoplasms, or congenital adrenal hyperplasia (CAH)
 Adrenocortical neoplasms
o More likely carcinomas than adenomas
o Often associated w/ hypercortisolism (mixed syndrome)
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Congenital adrenal hyperplasia (CAH)
o Several autosomal-recessive metabolic errors
o Results in deficiency/lack of enzyme involved in synthesis of cortical steroids
o Steroid precursors build up > diverted into other pathways
o 21-hydroxylase deficiency (most common)
 Salt-wasting (classic) adrenogenitalism
 Lack of hydroxylase > no synthesis of mineralocorticoids
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 Salt-wasting, hyponatremia, and hyperkalemia
 Acidosis, hypotension, CV collapse, possible death
 Virilization in women
Simple virilizing adrenogenitalism w/o salt wasting
 Generate enough mineralocorticoids to prevent salt wasting crisis
 Low levels of glucocorticoids synthesized fail to inhibit ACTH secretion
> testosterone increased > virilization
Nonclassical or late-onset adrenogenitalism
 Mild manifestations: hirsutism, acne, menstrual irregularities
Morphology
o CAH > adrenals b/l hyperplastic due to sustained ACTH
o Hyperplasia of corticotroph cells in anterior pituitary in most cases
o Adrenomedullary dysplasia in pts w/ severe salt-wasting 21-hydroxylase deficiency
Clinical Course
o Symptoms occur in perinatal period, later childhood, or less commonly in adulthood
o CAH should be suspected in any neonate w/ ambiguous genitalia
o Rx: exogenous glucocorticoids (+ mineralocorticoids for salt-wasting adrenogenitalism)
Adrenocortical Insufficiency
 Caused by primary adrenal disease or decreased stimulation of adrenals due to low ACTH (secondary)
 Primary Acute Adrenocortical Insufficiency (adrenal crisis)
 Crisis = pts w/ chronic adrenocortical insufficiency > precipitated by stress > requires immediate
increase in steroid output from glands incapable of responding
 Withdrawal = pts maintained on exogenous corticosteroids
 Massive adrenal hemorrhage = damages cortex sufficiently to cause insufficiency
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Waterhouse-Friderichsen Syndrome
 Overwhelming bacterial infection (classically Neisseria septicemia)
 Rapidly progressive hypotension > shock
 DIC associated w/ widespread purpura
 Rapidly developing adrenocortical insufficiency due to massive b/l adrenal hemorrhage
 Most common in children, but can occur at any age
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Primary Chronic Adrenocortical Insufficiency (Addison Disease)
 Resulting from progressive destruction of the adrenal cortex
 Clinical manifestations appear after >90% of cortex is destroyed
 Much more common in whites, and in women
 Pathogenesis
o Autoimmune adrenalitis (60-70% of cases)
 Autoimmune polyendocrine syndrome type 1 (APS1)
 AKA Autoimmune polyendocrinopathy, candidiasis, and ectodermal
dystrophy (APECED)
 AIRE mutation > T-cell tolerance comrpomised > autoimmunity
 Autoimmune polyendocrine syndrome type 2 (APS2)
 Starts in early adulthood
 Adrenal insufficiency + autoimmune thyroiditis or type 1 diabetes
 No candidiasis, ectodermal dysplasia, or autoimmune hypoparathyroid
o Infections
 Particularly tuberculosis and fungal infections
 Increased incidence in AIDS pts (due to CMV, M. avium, Kaposi sarcoma)
o Metastatic neoplasms involving the adrenals
 Commonly from lung and breast
 Also from GI, melanoma, and hematopoietic neoplasms
o Genetic causes of insufficiency
 Congenital adrenal hypoplasia
 Adrenoleukodystrophy
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Morphology
o Primary autoimmune adrenalitis = irregularly shrunken glands
o Tuberculous/fungal disease = granulomatous inflammatory rxn in adrenals
o Metastatic carcinoma = adrenals enlarged
Clinical Course
o Initial manifestation = weakness and easy fatigability, GI disturbances
o Primary disease > high ACTH > hyperpigmentation of skin
o Mineralocorticoids = hyperkalemia, hyponatremia, volume depletion, and hypotension
o Glucocorticoids = hypoglycemia
o Crisis = intractable vomiting, abdominal pain, hypotension, coma, vascular collapse
 Death if not treated w/ corticosteroids
Secondary Adrenocortical Insufficiency
 Disorder of the hypothalamus and pituitary that reduces output of ACTH
 Deficient cortisol and androgen output, but normal aldosterone synthesis
 Adrenals are decreased in size
 Cortex reduced to thin ribon of zone glomerulosa
 Medulla unaffected
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Adrenocortical Neoplasms
 May be responsible for hyperadrenalism
 Carcinomas associated w/
 Li-Fraumeni syndrome = TP53 mutation
 Beckwith-Wiedemann syndrome = disorder of epigenetic imprinting
 Functional adenomas associated w/ hyperaldosteronism and Cushing syndrome
 Virilizing are most likely carcinomas
 Morphology
 Adrenocortical adenomas
o Clinically silent, well-circumscribed
o Functional adenomas associated w/ atrophy of adjacent cortex
 Adrenocortical carcinomas
o Large and invasive
o More likely to be functional than adenomas
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Other Adrenal Lesions
 Adrenal cysts > abdominal mass and flank pain if large enough
 Cortical and medullary neoplasms > necrosis > cystic degeneration > "nonfunctional cysts"
 Adrenal myelolipomas = benign lesions of mature fat and hematopoietic cells
 Adrenal incidentaloma = mostly small nonsecreting cortical adenomas, clinically silent
Adrenal Medulla
o Chromaffin cells = catecholamines (epinephrine)
o Extra-adrenal paraganglia associated w/ autonomic nervous system
 Branchiomeric = parasympathetic, close to major arteries and cranial nerves, including carotid bodies
 Intravagal = parasympathetic, along vagus nerve
 Aorticosympathetic = sympathetic, along abdominal aorta (includes organs of Zuckerkandl)
o Pheochromocytoma
 Neoplasms composed of chromaffin cells
 Rare cause of surgically correctable HTN
 Rule of 10s
 10% are extra-adrenal (ex. organs of Zuckerkandl and carotid body)
 10% of sporadic cases are bilateral
 10% are biologically malignant
 10% are NOT associated w/ HTN
 25% are associated w/ germline mutations
o Genes that enhance growth factor receptor pathway signaling (RET, NF1)
o Genes that increase activity of transcription factor HIF-1α
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von Hippel-Lindau (VHL) syndrome = mutation in tumor suppressor protein needed for
degradation of HIF-1α
Genes encoding components of succinate dehydrogenase (SDHB, SDHC, SDHD) involved
in mitochondrial electron transport and oxygen sensing > upregulation of HIF-1α
Morphology
 Incubation of fresh tissue w/ potassium dichromate solution > turns tumor dark brown due to
oxidation of stored catecholamines > "chromaffin"
 Tumors composed of clusters of chromaffin cells or chief cells surrounded by supporting
sustentacular cells > small nests or alveoli (zellballen) supplied by a rich vascular network
 Nuclei are round/ovoid w/ stippled "salt and pepper" chromatin
 Metastases is only way to tell if they're malignant
Clinical Course
 HTN in 90% of pts
 2/3 of pts w/ HTN demonstrate paroxysmal episodes (abrupt elevation in bp, associated w/
tachycardia, palpitations, headache, sweating, tremor, sense of apprehension, pain in
chest/abdomen, nausea, vomiting)
 Paroxysms precipitated by emotional stress, exercise, changes in posture, and palpation of tumor
 BP elevation (due to sudden release of catecholamines) may precipitate CHF, pulmonary edema,
MI, ventricular fibrillation, or cerebrovascularaccident
 Catecholamine-induced myocardial instability and ventricular arrhythmias ("catecholamine
cardiomyopathy")
 Pheochromocytomas can sometimes secrete other hormones (ex. ACTH and somatostatin)
 Diagnosed by inc. urinary excretion of free catecholamines and their metabolites
 Rx: surgical excision after adrenergic-blocking agents to prevent HTN crisis
Multiple Endocrine Neoplasia Syndromes
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Group of inherited diseases > proliferative lesions (hyperplasia, adenomas, carcinomas) of multiple endocrine organs
Distinct features:
o Tumors occur at a younger age
o Tumors arise in multiple endocrine organs
o Tumors are often multifocal
o Tumors are preceded by asymptomatic stage of hyperplasia
o Tumors are more aggressive and recur in higher proportion of cases
Multiple Endocrine Neoplasia, Type I (Wermer syndrome)
o Characterized by abnormalities involving:
 Parathyroid > primary hyperparathyroidism (hyperplasia and adenomas)
 Pancreas > endocrine tumors (gastrinomas = Zollinger-Ellison & insulinomas = hypoglycemia/neurologic)
 Pituitary > prolactinoma most frequently. Also somatotrophin-secreting > acromegaly.
 Duodenum
 Also carcinoid tumors, thyroid and adrenocortical adenomas, and lipomas
o Caused by mutation in MEN1 tumor suppressor gene (encodes menin)
o Menin interacts w/ JunD and mixed-lineage leukemia (MLL) proteins
 JunD complex > blocks transcriptional activity of JunD > multiple endocrine neoplasia
 MLL complex > tumor promoting transcriptional complex > leukemias
o Clinical manifestations of overproduced peptide hormones:
 Insulinomas > recurrent hypoglycemia
 Zollinger-Ellison > intractable peptic ulcers
 PTH-induced hypercalcemia > nephrolithiasis
 Pituitary tumors > prolactin excess
Multiple Endocrine Neoplasia, Type 2
o Subclassified into 3 syndromes:
 MEN-2A (Sipple syndrome)
 Caused by germline gain-of-fxn in RET proto-oncogene
 Medullary carcinomas of the thyroid occur in 100% of pts
 Pheochromocytosis in 40-50% of pts
 Parathyroid hyperplasia > hypercalcemia or renal stones in 10-20% of pts
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MEN-2B
 Caused by germline mutation in RET (distinct from MEN-2A)
 Medullary thyroid carcinomas, usually multifocal and more aggressive than MEN-2A
 Pheochromocytomas
 Parathyroid hyperplasia NOT present
 Neuromas or ganglioneuromas involving skin, oral mucosa, eyes, respiratory tract, and GI tract
 Marfanoid habitus (long axial skeleton and hyperextensible joints)
 Familial medullary thyroid cancer
 Variant of MEN-2A
 Strong predisposition to medullary thyroid cancer, but not other manifestations
All pts w/ germline RET mutations are advised to undergo prophylactic thyroidectomy
Pineal Gland
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Composed of loose, neuroglial stroma enclosing nests of pineocytes (photosensory and neuroendocrine fxn)
Pineal gland = "third eye"
Principle secretory product = melatonin (control of circadian rhythms)
Most common tumors = germinomas (arising from embryonic germ cells)
Pinealomas
o Pineoblastomas
o Pineocytomas