Endocrine System - Part 1 (robbins)

Pathology (dr. Yabut) Endocrine Pathology – Part 1 (from Book) 09 January 08 THE ENDOCRINE SYSTEM

 contains highly integrated & widely distributed grp of organs that orchestrates a state of metabolic equilibrium or homeostasis  3 types of signaling: autocrine, paracrine, endocrine HORMONES: secreted molecules act on target cells distant from their site of synthesis Endocrine hormone: frequently carried by blood from site of release to its target FEEDBACK INHIBITION: activity of target tissue often downregulates the activity of the gland that secretes the stimulating hormone

HORMONE CLASSIFICATION (based on nature of receptors) 1. Hormones that trigger biochemical signals upon interacting w/ cell-surface receptors 2 Groups:

a) Peptide hormones – GH and Insulin b) Small molecules – Epinephrine  binding of hormones w/ cell-surface receptors leads to: in intracellular signaling molecules or Second Messengers (e.g. cAMP) prod’n of mediators from membrane phospholipids (e.g. inositol 1,4,5-triphosphate or IP3  shifts in the intracellular levels of ionized calcium - elevated levels of one or more of these can control proliferation, differentiation, survival, and functional activity of cells by regulating the expression of specific genes 2. Hormones that diffuse across the plasma membrane & interact w/ intracellular receptors in the cytosol or nucleus hormone-receptor complexes bind specifically to recognition elements in DNA w/c affects the expression of spec. target genes steroids (e.g. estrogen, progesterone, glucocorticoids thyroxine Processes that disturb normal activity of endocrine system:

2b1 (joysharcamsyna) & goldie

a. impaired synthesis or release of hormones b. abnormal interactions b/n hormones & target tissues c. abnormal responses of target organs General Classification of Endocrine Diseases a. diseases of underproduction or overproduction of hormones & their resulting biochemical & clinical consequences b. dse assoc w/ development of mass lesions (functional or assoc w/ overprod’n or underprod’n of hormones) PITUITARY GLAND  small, bean-shaped organ  measures 1cm (greatest diameter), weighs abt 0.5gm; enlarges during pregnancy  located at the base of the skull; lies nestled w/n the sella turcica near the otic chiasm & cavernous sinuses  attached to the hypothalamus by the pituitary stalk  plays a critical role in the regulation of most of other endocrine glands  Two morphologically & functionally distinct components: anterior lobe & posterior lobe ANTERIOR PITUITARY (ADENOHYPOPHYSIS)  abt 80% of the gland  embryologically from Rathke pouch (an extension of developing oral cavity)  has a portal vascular system – conduit for transport of hypothalamic releasing hormones from hypothalamus to the pituitary  hypothalamic neurons- have terminals in the median eminence where hormones are released into the portal system, from where they traverse the pituitary stalk and enter the ant pituitary  Positive-acting Releasing Factors – controls prod’n of most pituitary hormones  EXCEPT PROLACTIN – w/c is INHIBITORY through the axn of Dopamine  Pituiatry Growth Hormone – receives both stimulatory & inhibitory influences via the hypothalamus Five cell types in the adenohypophysis by immunostaining: 1- Somatotrophs: growth hormone (GH) – acidophils - constitute ½ of all hormone-producing cells in the ant pituitary 2- Lactotrophs (Mammotrophs): Prolactin (Prl) acidophils. 3- Corticotrophs: proopiomelanocortin (POMC) precursor for adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), b-endorphin, and blipotropin - basophils. 4- Thyrotrophs: thyroid stimulating hormone (TSH) basophils. 5- Gonadotrophs: basophils

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Pathology – Endocrine Pathology by Dr. Yabut a. follicle stimulating hormone (FSH) stimulates formation of Graafian follicles in the ovary b. luteinizing hormone (LH) – induces ovulation & formation of corpora lutea in the ovary POSTERIOR PITUITARY (NEUROHYPOPHYSIS)

 consists of PITUICYTES (modified glial cells) and AXONAL PROCESSES (extending from nerve cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus thru the pituitary stalk to the posterior lobe  neurons in the supraoptic & paraventricular nuclei produce ADH (vasopressin) & oxytocin  hormones are stored in the AXON TERMINALS; released into circulation w/ appropriate stimuli  OXYTOCIN – stimulates contraction of smooth muscle cells in the gravid mammary glands  ADH (Vasopressin) – nonpeptide; synthesized in the supraoptic nucleus; released from the axon terminals to the general circulation; STIMULI: plasma oncotic pressure, left atrial distention, exercise, certain emotional states

 from an outpouching of the floor of 3rd ventricle 

w/c grows downward alongside the ant lobe HAS DUAL CIRCULATION: in contrast to ant pituitary; composed of arteries & veins and a portal venous system linking the hypothalamus & the anterior lobe

CLINICAL MANIFESTATIONS OF PITUITARY DISEASE 1. HYPERPITUITARISM

 from excess secretion of trophic hormones  caused by: pituitary adenoma, hyperplasia, Ca of

ant pituitary, secretion of hormones by nonpituitary tumors, certain hypothalamic disorders 2. HYPOPITUITARISM

 from deficiency of trophic hormones  caused by: ischemic injury, surgery or radiation, inflammatory reactions  Nonfunctional Pituitary Adenomas – may encroach upon & destroy adjacent normal ant pituitary parenchyma & cause hypopituitarism 3. LOCAL MASS EFFECTS

 RADIOGRAPHIC ABNORMALITIES OF THE SELLA TURCICA including: sellar expansion, bony erosion, disruption of diaphragma sella close proximity of optic nerves and chiasm to the sella  expanding pituitary lesions often compress decussating fibers in the optic chiasm  visual field abnormalities (classically, defects in lateral (temporal) visual fields BITEMPORAL HEMIANOPSIA  Pituitary adenomas can produce SSX of ELEVATED ICP (intracranial pressure): headache, N/V  PITUITARY APOPLEXY: On occasion, ACUTE HEMMORHAGE into an adenoma is assoc w/ rapid enlargement of the lesion; can cause sudden death

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4. Disease of the posterior pituitary often come to clinical attention usually due to  or  of ADH PITUITARY ADENOMAS and HYPERPITUITARISM

 ADENOMA ARISING IN THE ANTERIOR LOBE –

most common cause of hyperpituitarism  Other less common causes: hyperplasia and Ca of anterior pituitary, secretion of hormones by extrapituitary tumors, hypothalamic disorders  PITUITARY ADENOMAS  FUNCTIONAL – assoc w/ hormone excess & clinical manifestations thereof  SILENT – immunohistochemical &/or ultrastructural demo of hormone prod’n @ the tissue level only, w/o clinical symptoms of hormone excess  both are usually composed of a single cell type & produce single predominant hormone  classified on the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue sections  some can secrete 2 hormones (GH & prolactin – most common combination)  rarely plurihormonal  may be hormone-negative, based on absence of immunohistochemical & ultrastructural demo of lineage-specific differentiation  silent & hormone-negative may cause hypopituitarism  responsible for abt 10% of intracranial neoplasms  discovered incidentally in up to 25% of routine autopsies  usually found in adults; peak incidence 30s to 50s  most occur as isolated lesions  microadenoma - <1cm  macroadenomas - >1cm  Genetic abnormalities assoc w/ Pituitary Adenomas  majority are monoclonal in origin; arise from single somatic cell; some plurihormonal tumors may arise from clonal expansion of primitive stem cells  G-protein mutations – possibly the best characterized molecular abnormalities  G-proteins  critical role in signal transduction  transmit signals from cell-surface receptors (GHRH receptors) to intracellular receptors (adenyl cyclase) w/c then generate 2nd messengers (cAMP)  heterotrimeric proteins, composed of a specific α-subunit that binds guanine nucleotide & interacts w/ both cell-surface & IC receptors  β- & γ-subunits – noncovalently bound to specific α-subunit  Gs – stimulatory G-protein; exists as an inactive protein in basal states, w/ GDP bound to guanine nucleotide-binding site of Gs α

Pathology – Endocrine Pathology by Dr. Yabut

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on interaxn w/ ligand-bound cell-surface







receptors, GDP dissociates & GTP binds to Gs α, thus activating the G-protein activation of Gs α  cAMP generation  potent mitogenic stimulus for various endocrine cell types  cellular proliferation & hormone synthesis & secretion activation of Gs α & cAMP generation = transient bcoz of an intrinsic GTPase activity in the α-subunit w/c hydrolizes GTP into GDP mutation in the α-subunit  interferes w/ intrinsic GTPase activity  constitutive activation of activation of Gs α , persistent cAMP generation & unchecked cellular proliferation gsp oncogene – mutant form of GNAS1; in minority of corticotroph adenomas; absent in thyrotroph, lactotroph, & gonadotroph adenomas Multiple endocrine neoplasia (MEN) syndrome – familial disorder assoc w/ tumors & hyperplasia of multiple endocrine organs MEN-1 – subtype; caused by germ line mutations of MEN1 gene on chromosome 11q13 Molecular abnormalities present in aggressive or advanced pituitary adenomas include: activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene

MORPHOLOGY (Pituitary Adenoma)  soft, well-circumscribed lesion that may be confined to the sella turcica  larger lesions typically extend superiorly thru the diaphragm sella into the suprasellar rgn  compression of optic chiasm & adjacent structures (e.g. cranial nerves)  expansion of adenoma  erodes sella turcica & anterior clinoid process  INVASIVE ADENOMAS – in 30% of cases  adenomas are not grossly encapsulated & infiltrate adjacent bone, dura, & brain (rarely) but no distant metastasis HISTOLOGIC  uniform, polygonal cells arrayed in sheets or cords  reticulin is sparse  soft, gelatinous consistency  nuclei may be uniform or pleomorphic  mitotic activity usually modest  cytoplasm – acidophilic, basophilic, chromophobic depends on type&amount of secretory product w/n the cells  CELLULAR MONOMORPHISM & the ABSENCE of a SIGNIFICANT RETICULIN NETWORK DISTINGUISH PITUITARY ADENOMAS FROM NON-NEOPLASTIC ANTERIOR PITUITARY PARENCHYMA

PROLACTINOMAS (LACTOTROPH ADENOMAS)  most frequent type of hyperfunctioning pituitary adenoma (30% of clinically recognized cases)  range from small microadenoma to large, expansile tumors assoc w/ substantial mass effect  microscopically, composed of weakly acidophilic or chromophobic cells (sparsely granulated prolactinoma)  rare prolactinomas are strongly acidophilic (densely granulated prolactinoma)  have a propensity to undergo DYSTROPHIC CALCIFICATION, ranging from isolated psammoma bodies to extensive calcification of virtually the entire tumor mass (“pituitary stone”)  Prolactin secretion of func. adenoma is characterized by its:  EFFICIENCY – even microadenomas secrete sufficient prolactin to cause hyperprolactinemia  PROPORTIONALITY – serum prolactin concentrations tend to correlate w/ the size of the adenoma  PROLACTINEMIA  serum levels of Prolactin  Cause: amenorrhea, galactorrhea, loss of libido, infertility  dx made readily in women than men (20-40yrs) bcoz of sensitivity of meses to disruption by hyperprolactinemia  HYPERPROLACTINEMIA: may result from causes other than prolactin-secreting pituitary adenomas physiologic hyperprolactinemia in pregnancy serum prolactin throughout pregnancy  peak at delivery nipple stimulation (suckling in lactating women) & response to stress  prolactin LACTOTROPH HYPERPLASIA pathologic hyperprolactinemia; when there is interference w/ normal dopamine inhibition of prolactin secretion w/c may occur as a result of damage to the dopaminergic neurons of the hypothalamus, pituitary stalk axn, or drugs that block dopa receptors on lactotroph cells STALK EFFECT: any mass in the suprasellar may disturb normal inhibitory influence of the hypothalamus on prolactin secretion resulting in hyperprolactinemia Drugs that cause HyperPRL: dopamine receptor antagonists (neuroleptic drugs such as phenothiazines, haloperidol);

Pathology – Endocrine Pathology by Dr. Yabut Anti-HPN such as Reserpine, w/c inhibit dopamine storage Other causes: estrogens, renal failure, hypothyroidism Tx: surgery (transsphenoidal) bromocriptine (dopamine receptor agonist) radiation a mild elevation in serum prolactin in a px w/ a pituitary adenoma DOES NOT necessarily indicate a prolactinsecreting tumor GROWTH HORMONE (SOMATOTROPH ADENOMAS)

 GH-secreting tumors – 2nd most common type of functioning pituitary adenoma  40% express a mutant GTPase-deficient α-subunit of the G-protein, Gs  2 types of GH-containing adenomas (histologic) Densely granulated – cells are monomorphic, acidophilic, retain strong cytoplasmic GH reactivity, cytokeartin staining in perinuclear distribution Sparsely granulated – chromophobe cells w/ nuclear & cytologic pleomorphism, retain focal & weak GH reactivity  Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth factor (IGF-1 or somatomedin C) w/c causes many of the clinical manifestations Gigantism; GH excess occurs in children (before closure of epiphyses). generalized increase in body size disproportionately long arms and legs Acromegaly;

adult onset excess growth hormone (GH) Þ enlargement of the skull, facial bones, jaw, hands, feet, soft tissues & organs. diabetes, hypertension, muscle weakness, arthritis, gonadal dysfunction, cardiovascular disease HYPEROSTOSIS - bone density; spine&hips PROGNATHISM – enlargement of the jaw resulting to protrusion w/ broadening of lower face  dx of pituitary GH excess relies on documentation of serum GH & IGF-1  failure to suppress GH prod’n in response to an oral load of glucose is one o fthe most sensitive tests for acromegaly TREATMENT: Goals: to restore GH levels to normal & to decrease symptoms referable to a pituitary mass lesion while not causing hypopotuitarism surgically, radiation therapy, drug therapy

CORTICOTROPH CELL ADENOMAS

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 usually small microadenomas at time of dx  most often basophilic & occasionally chromophobic  +PAS: presence of carbohydrate in preopiomelanocorticotropin (POMC), the ACTH precursor molecule  variable immunoreactivity for POMC & ACTH & βendorphin Cushing’s disease.

 ACTH

secretion of cortisol from the adrenal glands hypercortisolism  moon face, buffalo hump, truncal obesity, abdominal striae  diabetes mellitus, hirsutism and amenorrhea (ACTH stimulates androgen secretion)  increased skin pigmentation (MSH is secreted with pituitary ACTH), hypertension, muscle weakness Nelson Syndrome  when large destructive adenomas develop in pts after surgical removal of the adrenal glands for tx of Cushing syndrome  occurs due to loss of inhibitory effect of adrenal corticosteroids on pre-existing corticotroph microadenoma  hypercortisolism does not develop  w/ mass effects of pituitary tumor  hyperpigmentation bcoz of stimulatory effect of other products of ACTH precursor on melanocytes OTHER ANTERIOR PITUITARY ADENOMAS  pituitary adenomas may elaborate >1 hormone  some cases, unusual plurihormonal adenomas are capable of secreting multiple hormones; usually aggressive LESS FREQUENT FUNCTIONING ADENOMA GONADOTROPH (LH-producing & FSH-producing)  diffcult to recognize bcoz of inefficient & variable hormone prod’n & secretory products do not cause recognizable clinical syndrome  commonly in middle-aged men & women when they are large enough  Neurologic symptoms: impaired vision, headaches, diplopia, pituitary apoplexy  pituitary hormone deficiencies such as impaired secretion of LH w/c causes energy&libido due to testosterone & amenorrhea in premenopausal women  paradoxically assoc w/ 2º gonadal hypofunction  most are large w/ chromophobic cells  neoplastic cells demonstrate immunoreactivity for common gonadotropin α-subunit & the β-FSH & βLH subunits  FSH – usual predominant secreted hormone  “Null Cell Adenomas” - hormone-negative adenomas THYROTROPH (TSH-producing)  rare (only 1%)

Pathology – Endocrine Pathology by Dr. Yabut

 chromophobic or basophilic  rare cause of hyperthyroidism NONFUNCTIONING PITUITARY ADENOMA  comprise both clinically silent counterparts of the func adenoma and true hormone-negative adenomas  approx 25%  in the past, classified as “null cell adenomas” bcz of inability to demo markers of differentiation  MASS EFFECTS – typical presentation  lesions may also compromise the residual ant pituitary sufficiently to cause hypopituitarism  may occur as a result of gradual enlargement of adenoma or after abrupt enlargement of the tumor bcoz of acute hemorrhage (pituitary apoplexy)  pituitary CA are rare; most not functional  range from well-differentiated (resemble atypical adenoma) to poorly diff (variable degrees of pleomorphism & the characteristic features Ca in other locations)  Dx requires demo of metastasis to lymph nodes, bone, liver,.. HYPOPITUITARISM

 refers to  secretion of pituitary hormones w/c can result from diseases of the hypothalamus or pituitary  hypofunction of ant pituitary occurs when 75% of the parenchyma is lost/absent  may be congenital or result of variety of acquired abnormalities intrinsic to the pituitary  accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus (DI) is almost always of hypothalamic origin Causes of Hypofunction Tumors & other Mass Lesion  pituitary adenomas  benign tumors arising w/n sella  1º & metastatic malignancies  cysts  any mass lesion in sella can cause damage by exerting pressure on adjacent pituitary cells Pituitary Surgery or Radiation  excision of adenoma may extend to nonadenomatous pituitary  radiation used to prevent regrowth of residual tumor after surgery can damage nonadenomatous pituitary Pituitary Apoplexy  sudden hemorrhage into the pituitary gland often occurring into a pituitary adenoma  causes the sudden onset of excruciating headache, diplopia owing to pressure on oculomotor nerves, hypopituitarism  severe cases, can cause CV collapse, loss of consciousness, sudden death  true neurosurgical emergency  Ischemic necrosis of the Pituitary & Sheehan Syndrome

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 impt cause of pituitary insufficiency  Sheehan Syndrome or Post-partum necrosis of ant pituitary – most common form of clinically significant ischemic necrosis of ant pituitary Rathke Cleft Cyst  lined by ciliated cuboidal epith w/ occasional goblet cells & ant pituitary cells  can accumulate proteinaceous fluid & expand, compromising the normal gland Empty Sella Syndrome  results from any condition that destroys part or all of the pituitary gland (e.g. ablation of pituitary by surgery or radiation)  refers to the presence of an empty sella turcica not filled w/ pituitary tissue  PRIMARY EMPTY SELLA – defect in the diaphragma sella that allows the arachnoid matter & CSF to herniated into the sella  expansion of sella & compression of pituitary - affected patient are obese women w/ hx of multiple pregnancies - may be assoc w/ visual field defects & occ w/ endocrine abnormalities such as hyperprolactinemia  SECONDARY EMPTY SELLA – a mass (pituitary adenoma) enlarges the sella, but is surgically removed or undergoes spontaneous necrosis leading to loss of pituitary func. hypopituitarism can result from the tx of spontaneous infarction Genetic Defetcs  mutations in pit-1 (pituitary transcription factor), result in combined deficiency of GH, prolactin, & TSH  d/o that interfere w/ the delivery of pituitary hormone-releasing factors from the hypothalamus may also cause hypofunction of ant. pituitary (e.g. pituitary tumors)  any disease involving the hypothalamus can alter secretion of 1 or more of the hypothalamic hormones that influence secretion of the corresponding pituitary hormones  any of these conditions can also secretion of ADH diabetes insipidus (DI) Hypothalamic lesions that cause hypopituitarism: a. TUMORS:

 benign lesions that arise from hypothalamus (e.g.

craniopharyngiomas);  malignant tumors that metastasize (e.g. breast&lung Ca)  hypothalamic hormone deficiency can ensue when brain or nasopharyngeal tumors are treated w/ radiation b. INFLAMMATORY D/O & INFECTIONS  sarcoidosis, tuberculous meningitis can cause ant pituitary hormone deficiency & DI  clinical manifestations of ant. pituitary hypofunc depend on SPECIFIC hormone/s that are lacking  GH deficiency  pituitary dwarfism

Pathology – Endocrine Pathology by Dr. Yabut

 GnRH deficiency  amenorrhea & infertility in women; libido, impotence, & loss of pubic or axillary hair in men  TSH def  symptoms of hypothyroidism

 ACTH def  symptoms of hypoaldrenalism  prolactin def  failure of post-partum lactation  Melanocyte-stimulating hormone (MSH) – from the anterior pituitary; synthesized from the same precursor of ACTH  Pallor – one of the manifestations of hypopituitarism due to loss of stimulatory effects of MSH on melanocytes POSTERIOR PITUITARY SYNDROMES DIABETES INSIPIDUS (DI)  due to ADH deficiency  CENTRAL DI  different from NEPHROGENIC DI w/c is a result of renal tubular unresponsiveness to circulating ADH  clinical manifestations are similar w/c include: excretion of large volumes of DILUTE urine w/ inappropriately LOW specific gravity serum Na & osmolality are  due to excessive renal loss of free water  thirst & polydipsia  excessive urination (polyuria) due to inability of kidneys to resorb water properly from the urine  can result from: head trauma, tumors, inflammatory d/o or surgical procedures of the hypothalamus & pituitary;  can also be idiopathic  pt who can drink water  compensate for urinary losses  pt who are obtunded, bedridden, limited ability to obtain water may develop life-threatening dehydration SYNDROME of INAPPROPRIATE ADH (SLADH) SECRETION

 ADH excess  resorption of excessive amts of free water  HYPONATREMIA

 Frequent causes:



 secretion of ectopic ADH by malignant neoplasms  (particularly SCC of the lungs)  non-neoplastic dses of the lungs  local injury to the hypothalamus or post. pituitary Clinical manifestations:  hyponatremia, cerebral edema, resultant neurologic dysfunction

 Total body water is   Blood volume remains Normal  peripheral edema does not develop HYPOTHALAMIC SUPRASELLAR TUMORS  neoplasms in this location may induce hypofunction or hyperfunction of the anterior pituitary, DI, or combinations of these  most commonly implicated lesions are:

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gliomas & craniopharyngiomas CRANIOPHARYNGIOMA thought be derived from vestigial remnants of Rathke pouch slow-growing tumors; acct for 1-5% of intracranial tumors small minority arise w/in the sella; but most are Suprasellar w/ or w/o an intrasellar extension w/ bimodal age distribution: 1st peak @ 5-15 yrs then 2nd peak in adults @ 60 yrs – older Children usually present w/ endocrine deficiencies such as growth retardation; Adults w/ visual disturbances pituitary hormonal deficiencies, including DI, are common pts have an excellent recurrence-free & overall survival tumors>5cm higher recurrence rate adamantinomatous tumors higher frequency of brain invasion but does not necessarily correlate w/ an adverse prognosis malignant transformation into squamous Ca are rare & usually occurs postradiation THYROID GLAND  consists of 2 bulky lateral lobes connected by a relatively thin Isthmus  located below & anterior to the larynx  Wt of normal adult thyroid = 15 – 25 gm  normal structural variations include: presence of pyramidal lobe w/c is a remnant of the thyroglossal duct above the isthmus  has a rich intraglandular capillary network supplied by Superior & Inferior thyroidal arteries  nerve fibers from Cervical Sympathetic Ganglia indirectly influence thyroid secretion by acting on blood vessels  divided by thin, fibrous sepate into lobules composed of abt 20-40 evenly dispersed follicles  Normal follicle size = 50 -500 µm  follicles: lined by cuboidal to low columnar epith, filled w/ PAS-positive thyroglobulin  develops from an evagination of the developing pharyngeal epith that descends as part of the thyroglossal duct from the foramen cecum @ the base of the tongue to its normal position in the anterior neck  Ectopic thyroid tissue- commonly located @ the base of the tongue (lingual thyroid) or at other sites abnormally high in the neck  Excessive descent - substernal thyroid glands  clinical significance of lesions lies in distinguishing them from metastatic thyroid Ca or primary thyroid malignancy  Total Migration Failure - pts w/ lingual thyroids in w/c the ectopic thyroid tissue is the ONLY thyroid tissue thus removal of lingual thyroid results to Symptomatic Hypothyroidism  Malformations of branchial pouch differentiation – intrathyroidal sites of the thymus or parathyroid glands

Pathology – Endocrine Pathology by Dr. Yabut  these deviations bcome evident in pts who has total thyroidectomy & subsequently develops hypoparathyroidism  TSH – released by thyrotrophs in the Ant. Pituitary into the circulation inresponse to trophic factors from hypothalamus  binding of TSH & its receptor on the thyroid follicular epithactivation and conformational change in the receptor  association w/ a stimulatory G-protein  activation of G-protein  in intracellular cAMP  stimulates thyroid growth, hormone synthesis & release via cAMP-dependent protein kinases  Thyroid Autonomy & hyperfunction – results from dissociation of thyroid hormone synthesis & release from the controlled influence of TSH-signaling pathways  Thyroid follicular epith cells – convert thyroglobulin into T4 (thyroxine) & lesser amts of T3 (triiodothyronine)  T4 and T3 – released into systemic circulation where most of these peptides are reversibly bound to circulating plasma proteins such as TBG (thyroxinebinding globulin) & transthyretin for transport to peripheral tissue  Binding proteins – maintain serum unbound (“free”) T4 &T3 w/in narrow limits; ensure hormones are readily available to the tissues  in the periphery, majority of free T4 is DEIODINATED to T3  T3 – binds to thyroid hormone nuclear receptors in target cells w/ 10x> affinity than T4 & proportionately > activity  The interaxn of thyroid hormone w/ its nuclear thyroid hormone receptor (TR) results inte formation of a multi-protein hormone-receptor complex that binds to thyroid hormone response elements (TREs) in target genes, regulating their transcription.  Cellular effects of Thyroid hormone: up-regulation of carbohydrate & lipid catabolism & stimulation of protein synthesis in wide range of cells  Net result =  in Basal Metabolic Rate  Impt Func of Thyroid hormone: in brain dev’t, since absence of TH during fetal & neonatal periods may profoundly interfere w/ intellectual growth  Thyroid gland is one of the most responsive organs & contains the largest store of hormones of any endocrine gland  responds to stimuli & in constant state of adaptation  gland ↑in size & becomes more active during: pregnancy, puberty, & presence of 7easurement stress from any source  functional lability is reflected in transient hyperplasia of thyroidal epithelium at this time, thyroglobulin is resorbed; follicular cells bcome tall & more columnar, sometimes forming small, infolded buds, or papillae INVOLUTION – happens when stress abates; height of epith falls, colloid accumulates, follicular cells return to normal size & architecture failure of this balance b/n hyperplasia & involution can produce major or minor deviations from usual histo  GOITROGENS – various chemical agents w/c can inhiit the normal func of thyroid gland; suppress T4 & T3

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levels →↑TSH → hyperplastic enlargement of gland (goiter)  PROPYLTHIOURACIL – antithyroid agent; inhibits oxidation of iodide; blocks prod’n of thyr. hormone; (parenthetically) inhibits peripheral deiondination of circulating T4 into T3 thus ameliorating symptoms of thyr. hormone excess  IODIDE – given to pts w/ thyroid hyperfunc; blocks the release of thyroid hormones thru diff mechanisms; (in large doses) inhibit proteolysis of thyroglobulin thus thyr hormone is synthesized 7 incorporated w/n increasing amts of colloid, but not released into the blood  PARAFOLLICULAR CELLS (C CELLS) – synthesize & secrete calcitonin w/c promotes absorption of calcium by the skeletal system & ihibits resorption of bone by osteoclast PATHOLOGY

 most dse of thyroid are amenable to medical or surgical tx  Include: excessive release of thyroid hormones (hyperthyroidism); those assoc w/ thyroid hormone deficiency (hypothyroidism); mass lesions of the thyroid HYPERTHYROIDISM THYROTOXICOSIS

 hypermetabolic state caused by ↑ circulating levels of T4 & T3  often referred to as Hyperthyroidism bcoz most 7easur cause is hyperfunction of thyroid gland  (in other conditions) oversupply is related to either ecessive release of preformed thyroid hormone (e.g. thyroiditis) or an extrathyroidal source  so, hyperthyroidism is only one (most common) cause of thyrotoxicosis  3 most common causes of thyrotoxicosis (also assoc w/ hyperfunc of the gland): - Diffuse hyperplasia of the thyoid assoc w/ Graves’ Dse (accts for 85%of cases) - hyperfunctional multinodular goiter - hyperfunctional adenoma of the thyroid The term Primary & Secondary Hyperthyroidism are used to designate hyperthyroidism arising from an intrinsic thyroid abnormality & that arising from processes outside the thyroid such as TSH-secreting pituitary tumor CLINICAL COURSE

 clinical manifestations: protean; changes referable to Hypermetabolic state induced by excess thyroid hormone and also those related to overactivityof 7easurement nervous system (i.e. increase in the βadrenergic “tone)  excessive levels of thyr hormone → ↑basal metabolic rate  skin: warm, soft, lushed due to ↑blood flow & peripheral vasodilation to ↑heat loss

Pathology – Endocrine Pathology by Dr. Yabut  heat intolerance is common; ↑sweating due to higher levels of calorigenesis; weight loss despite ↑appetite  CARDIAC manifestations: among the earliest & most consistent feature  ↑CO due to ↑ cardiac contractility & ↑peripheral oxygen requirements  tachycardia, palpitations, cardiomegaly are common  arrythmias (Atrial fib) occur frequently/more common in  elderly pts  CHF may develop esp in older pts  MYOCARDIAL changes: foci of lymphocytic & eosinophilic infiltration; mild fibrosis in th interstitium; fatty changes in myofibers; ↑size & no. of mitochondria  THYROTOXIC DILATED CARDIOMYOPATHYcondition in w/c some pts develop reversible diastolic dysfunction & “low-output” failure  overactivity of sympathetic nervous system → tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, insomnia  THYROID MYOPATHY (common)- proximal muscle weakness w/ ↓muscle mass  Ocular changes: wide, staring gaze, lid lag (due to sympathetic overstimulation of levator palpebrae superioris)  True Thyroid Ophthalmopathy assoc w/ proptosis – seen only in graves’ disease  sympathetic hyperstimulation of GIT – hypermotility, malabsorption, diarrhea  Skeletal system: thyroid hormone stimulates bone resorption → ↑porosity of cortical bone & ↓vol of trabecular bone  Net Effect: Osteoporosis; ↑risk of fractures in pts w/ chronic hyperthyroidism  Other findings: atrophy of skeletal muscle; fatty infiltration & focal interstitial lymphocytic infiltrates; minimal liver enlargement due to fatty changes in hepatocytes; generalized lymphoid hyperplasia w/ lymphadenopathy  THYROID STORM  abrupt onset of severe hyperthyroidism  occur most commonly in pts w/ underlying Graves’ dse & probably results from acute elevation in catecholamine levels (e.g. during infections, surgery, cessation of antithyroid medication, any form of stress)  pts often febrile, w/ tachychardia  untreated pts die of cardiac arrythmias =(  APATHETIC HYPERTHYROIDISM • refers to thyrotoxicosis in the elderly; old age & various comorbidities may blunt the typical features • Dx is usually made in during lab work-up for unexplained wt loss or worsening of CV dse  Dx of hyperthyroidism is made using both clinical & lab  The measurement of serum TSH concentration using sensitive TSH (sTSH) assays provides the most useful single screening test for hyperthyroidism  low TSH – confirmed w/ measurement of free T4 w/c is ↑

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 In some pts, hyperthyroidism results from

predominantly from ↑ circulating levels of T3 (“T3 toxicosis”) •free T4 levels may be decreased; direct 8easurement of serum T3 may be useful  in rare cases of Pituitary (Secondary) Hyperthyroidism, TSH levels are either normal or raised  TRH STIMULATION TEST – deterimining TSH levels after injection of TRH used in the evaluation of cases of suspected hyperthyroidism w/ equivocal changes in the baseline serum TSH level  Normal rise in TSH after TRH injection excludes 2˚hyperthryoidism  confirmed dx of thyrotoxicosis followed by measurement of radioactive iodine uptake by thyroid gland to determine etiology  E.g. ◦in Graves’ – there may be diffusely uptake in the whole gland ◦toxic adenoma - uptake in a solitary nodule ◦thyroiditis - uptake  Therapeutic options: •β-blockers to control symptoms induced by  adrenegic tone •Thionamide to block new hormone synthesis •Iodine sol’n to block the release of thyroid hormone and agents that inhibit peripheral conversion of T4 to T3 •Radioiodine incorporated in thyroid tissue, results in ablation of thyroid func over a period of 6-18 wks HYPOTHYROIDISM  caused by any structural or functional derangement that interferes w/ the prod’n of adequate levels of thyroid hormone  can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis  also divided into 1º or 2º hypothyroidism  Primary Hypothyroidism – accts for majority of the cases; can be Thyroprivic (due to absence or loss of thyroid parenchyma) or Goitrous (due to enlargement of thyroid gland under the influence of TSH) Causes of Primary Hypothyroidism: 1. Surgical or Radiation-induced ablation of thyroid parenchyma  total thyroidectomy fro the tx of hyperthyroidism of a primary neoplasm can lead to hypothyroidism  gland may be ablated by radiation (radioiodine administered for tx of hyperthyroidism, or exogenous irradiation such as external radiation therapy to the neck) 2. Autoimmune Hypothyroidism  most common cause of goitrous hypothyroidism in iodine-sufficient areas  vast majority of cases are due to Hashimoto thyroiditis  circulating antibodies, incl. anti-TSH receptor autoantibodies are commonly found

Pathology – Endocrine Pathology by Dr. Yabut  some pts may have circulating anti-TSH antibodies but do not present the goitrous enlargement or lymphocytic infiltrate characteristic of Hashimoto 3. Drugs  given intentionally to  thyroid secretion e.g. methimazole & propylthiouracil  agents used to treat nonthyroid conditions e.g. lithium, p-aminosalicylic acid 4. Inborn errors of thyroid metabolsim  uncommon cause of goitrous hypothyroidism (dyshormonogenetic goiter)  Any deficiency on the ff step of Thyroid hormone synthesis: a. iodide transport defect b. organification defect c. dehalogenase effect d. iodotyrosine coupling defect  PENDRED SYNDROME – deficiency in the process of organification of iodine w/c involves binding of oxidized iodide w/ tirosyl residues in thyroglobulin, wherein goitrous hypothyroidism is accompanied by sensorineural deafness 5. Thyroid Hormone Resistance Syndrome  rare, autosomal dominant d/o  cause: inherited mutations in the TR w/c abolish the ability of the receptor to bind thyroid hormones  pts have generalized resistance to thyroid hormone despite high circulating levels of T4&T3  TSH levels are high since pituritary is also resistant to feedback from thyroid hormones  Thyroid Agenesis – complete absence of thyroid parenchyma  Thyroid Hypoplasia – gland is reduced in size  newly recognized cause: mutations in the TSH receptor assoc w/ hypoplastic thyroid gland  Mutations in 2 Transcription factors that are expressed in the developing thyroid & regulate follicular differentiation (thyroid transcription factor-2 or TTF-2 and Paired Homeobox-8 or PAX-8) reported in pts w/ thyroid agenesis  Thyroid agenesis caused by TTF-2 mutations is usually assoc w/ CLEFT PALATE 6. Secondary Hypothyroidism is caused by TSH deficiency, & Tertiary (Central) Hypothyroidism is caused by TRH deficiency  can result from any of the causes of hypopituitarism  frequent cause: Pituitary Tumor  other causes: postpartum pituitary necrosis; trauma; nonpituitary tumors  Tertiary (Central) hypothyroidism – can be caused by any d/o that damages the hypothalamus or interferes w/ hypothalamic-pituitary portal blood flow, thereby preventing delivery of TRH to the pituitary  can result from: hypothalamic damage from tumors, trauma, radiation therapy, infiltrative dse  Clsssic clinical manifestations: CRETINISM & MYXEDEMA CRETINISM

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 hypothyroidism that develops in infancy or early childhood  Gk. Chrétien; Christian or Christlike; they were so mentally retarded as to be incapable of sinning..  in the past, occurred primarily in areas w/ endemic dietary iodine deficiency but became much less frequent in recent years due to widespread supplementation of foods w/ iodine  may also be due to inborn errors in metabolism 9e.g. enzyme deficiencies) that interfere w/ the biosynthesis of normal levels of thyroid hormone (sporadic cretinism)  Clinical features: impaired dev’t of skeletal system & CNS manifested by severe mental retardation, short stature, coarse facial features, protruding tongue, umbilical hernia  severity of mental impairment appears to be related to time of occurrence of thyroid deficiency in utero  since T4&T3 normally cross the placenta & are critical to fetal brain dev’t  maternal thyroid deficiency before fetal thyroid gland dev’t  severe mental retardation  reduction in maternal thyroid hormones later in pregnancy after fetal thyroid developed  allows normal brain dev’t MYXEDEMA (Gull Disease)  hypothyroidism in older child or adult  clinical manifestations vary w/ age  Clinical features: slowing of physical & mental activity  Initial symptoms: generalized fatigue, apathy, mental sluggishness (may mimic depression in the early stages)  speech & intellectual func become slowed  Pts are listless, cold-intolerant, frequently overweight  Reduced CO probably contribute to shortness of breath &  exercise capacity

 constipation & sweating (due to  sympathetic activity  skin is cool & pale due to  blood flow Histologic:  accumulation of matrix substances such as glycosaminoglycans & hyaluronic acid in the skin, subcutaneous tissue & some visceral sites  edema, broadening & coarsening of facial features, enlargement of tongue, deepening of voice Laboratory:  measurement of serum TSH level  most sensitive screening test for this d/o  TSH level is  in 1ºhypothyroidism due to loss of feedback inhibition of TRH prod/n by the hypothalamus & TSH prod/n by pituitary  TSH level is NOT  in pts w/ hypothyroidism due to 1ºhypothalamic or pituitary dse  T4 levels are  in pts w/ hypothyroidism of ANY ORIGIN THYROIDITIS

Pathology – Endocrine Pathology by Dr. Yabut  inflammation of the thyroid gland; encompasses a diverse grp of d/o characterized by some form of thyroid inflammation  include conditions that result in acute illness w/ severe thyroid pain (e.g. infectious thyroiditis, subacute granulomatous thyroiditis) and;  d/o in w/c there is relatively little inflammation & illness is manifested primarily by thyroid dysfunction (e.g. subacute lymphocytic thyroiditis & fibrous (Reidel) thyroiditis)  INFECTIOUS THYROIDITIS  either acute or chronic  Acute infections: reach the thyroid via hematogenous spread or thru direct seeding of the gland, such as via a fistula from the piriform sinus adjacent to the larynx  Chronic: frequently occur in immunocompromised pts; includes mycobacterial, fungal, Pneumocystis infections  sudden onset of neck pain & tenderness in the area of the gland accompanied by fever, chills, & other signs of infection  can be self-limited or can be controlled w/ appropriate therapy  thyroid func usually not significantly affected  there are few residual effects except for possible small foci of scarring HASHIMOTO THYROIDITIS  CHRONIC LYMPHOCYTIC THYROIDITIS  most common cause of hypothyroidism in iodinesufficient areas  characterized by: Gradual Thyroid Failure due to autoimmune destruction of thyroid gland  in 1912, Hashimoto reported pts w/ goiter & intense lymphocytic infiltration of the thyroid (struma lymphomatosa)  most prevalent b/n 45-65 yrs  more common in women; female predominance 10:1 to 20:1  can also occur in children; major cause of NONENDEMIC GOITER in children  pattern of inheritance in non-Mendelian; likely to be influenced by subtle variations in the functions of multiple genes  concordance rate: 30-60% (monozygotic twins); up to 50% of asymptomatic 1º relatives of Hashimoto pts have circulating antithyroid antibodies  Chromosomal abnormalities assoc w/ Hashimoto:  Turner Syndrome – have a high prevalence of circulating antithyroid antibodies; 20% develops subclinical or clinical hypothyroidism that is indistinguishable from Hashimoto  Down Syndrome (Trisomy 21) -  risk of developing Hashimoto & hypothyroidism  link b/n polymorphism in HLA-DR3 & HLA-DR5 alleles and Hashimoto was reported but association is weak  genomewide linkage analyses provided eveidence on several susceptible loci such as on chromosome 6p & 12q may harbor genes predisposing to this d/o

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PATHOGENESIS  autoimmune disease; immune system reacts against a variety of thyroid antigens  Overriding feature: PROGRESSIVE DEPLETION OF THYROID EPITHELIAL CELLS w/c are gradually replaced by mononuclear cell infiltration & fibrosis  Initiating event: Sensitization of autoreactive CD4+ Thelper cells to thyroid antigens

Hashimoto thyroiditis, Subacute thyroiditis, Graves disease  EFFECTOR MECHANISMS for THYROCYTE DEATH : a. CD8+ cytotoxic T cell-mediated cell death  may cause thyrocyte destruction by Exocytosis of perforin/granzyme granules or Engagement of death receptors specifically CD95 (Fas) on the target cell b. Cytokine-mediated cell death  CD4+ T cells produce inflammatory cytokines such as IFN-γ in the immediate thyrocyte milieu  recruitment & activation of macrophages & damage to follicles c. Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, antihtyroid peroxidase antibodies) followed by antibody-dependent cellmediated cytotoxicity (ADCC) CLINICAL COURSE  painless enlargement of the thyroid usually assoc w/ some degree of hypothyroidism in a middle-aged woman  enlargement of gland is symmetric & diffuse but may be sufficiently localize din some cases (suspicion of neoplasm)  usual course: develops gradually  HASHITOXICOSIS - in some cases of Hashimoto, it may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles w/ 2º release of thyroid hormones  during this phase: free T4 & T3; TSH; radioactive iodine uptake  as hypothyroidism supervenes, T4 & T3 progressively fall accompanied by compensatory  in TSH  pts w/ Hashimoto are at  risk for developing other concomitant autoimmune dses: both endocrine (type 1 diabetes, autoimmune adrenalitis) & nonendocrine ( SLE, myasthenia gravis, Sjögren syndrome) and also B-cell non-Hodgkin lymphoma  there is no established risk for developing thyroid epithelial neoplasms

Pathology – Endocrine Pathology by Dr. Yabut

MORPHOLOGY  thyroid often diffusely enlarged  capsule is intact and gland is well-demarcated from adjacent structures  cut surface is pale, yellow-tan, firm, somewhat nodular  Histologic: extensive infiltration of parenchyma by a Mononuclear Inflammatory Infiltrate containing small lymphocytes, plasma cell, well-developed germinal centers  thyroid follicles are atrophic, lined in many areas by epithelial cells w/ presence of abundant eosinophilic, granular cytoplasm termed Hürthle cells  metaplastic response of the normally low cuboidal follicular epith to ongoing injury  FNAB: (+) Hurthle cells in conjunction w/ a heterogenous pop’n of lymphocytes (characteristic of Hashimoto)  “Classic” Hashimoto – interstitial connective tissue is  & may be abundant  FIBROUS VARIANT: severe thyroid follicular atrophy & dense “keloid-like” fibrosis, w/ broad bands of acellular collagen encompassing residual thyroid tissue  fibrosis does not extend beyond the capsule  remnant thyroid parenchyma demonstrates features of chronic lymphocytic thyroiditis SUBACUTE (GRANULOMATOUS) THYROIDITIS  aka De Quervain thyroiditis  occurs much less frequently than Hashimoto  most common b/n 30-50 yrs  female predominance of 3:1 to 5:1 PATHOGENESIS  believed to be caused by a viral infection or a postviral inflammatory process  majority of pts have Hx of upper respi. infection  has seasonal incidence, peaking in the summer  clusters of cases have been reported in assoc w/ coxsackievirus, mumps, measles, adenovirus, & other viral illnesses  pathogenesis is unclear but one model suggests that it results from: a viral infection provides an antigen (viral or thyroid antigen) that is released 2º to virus-induced host tissue damage  antigen stimulates cytotoxic T lymphocytes  damage thyroid follicular cells  immune response is virus-initiated & not selfperpetuating so the process is limited CLINICAL COURSE  may be sudden or gradual  pain in the neck w/c may radiate to upper neck, jaw, throat, or ears particularly when swallowing  variable enlargement of thyroid accompanied by fever, fatigue, malaise, anorexia, & myalgia

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 thyroid inflammation & hyperthyroidism are transient (diminishing w/in 2-6 wks even w/o tx)  may be followed by a period of transient, asymptomatic hypothyroidism (2-8wks) but recovery is virtually complete  the transient hyperthyroidism si due to disruption of thyroid follicles & release of excessive thyroid hormone  nearly all pts have high serum T4&T3 w/ low TSH  radioactive iodine uptake is low due to suppression of TSH  after recovery, in 6-8wks, normal thyroid fnc returns MORPHOLOGY  gland may be unilaterally or bilaterally enlarged & firm w/ an intact capsule  may be slightly adherent o surrounding structures  involved areas are firm & yellow-white instead of the normal rubbery, brown thyroid tissue  Histologic: changes are patchy & depend on disease stage  early in the active inflammatory phase: scattered follicles may be entirely disrupted & replaced by neutrophils forming microabscesses  more characteristic features appear later in the form of aggregations of lymphocytes, histiocytes, plasma cells about collapsed & damaged thyroid follicles  multinucleate giant cells enclose naked pools or fragments of colloid  granulomatous  later stages: chronic inflammatory infiltrate & fibrosis may replace foci of injury SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS  aka Painless Thyroiditis or Silent Thyroiditis  an uncommon cause of hyperthyroidism  mild hyperthyroidism or goitorus enlargement of gland (or both)  can occur at any age but often seen in middle-aged adult & more common in women esp during postpartum period (postpartum thyroiditis)  pathogenesis is unknown  autoimmune basis has been suggested bcoz some pts have levels of antibodies to thyroglobulin & thyroid peroxidase or; family hx of thyroid autoimmune dse  occasionally, dse develops into overt chronic autoimmune thyroiditis several yrs later  no particular viral or other agent CLINICAL COURSE  Hyperthyroidism – principal clinical manifestation  symptoms develop over 1-2 wks and last from 2-8wks before subsiding  palpitations, tachycardia, tremor, weakness, fatigue (common findings of hyperthyroidism)  thyroid gland not usually tender but is minimally & diffusely enlarged  no infiltrative ophthalmopathy nor other manifestations of Graves  pts w/ one episode of postpartum thyroiditis are at  risk of recurrence ff subsequent pregnancies  minority of pts progress to hypothyroidism

Pathology – Endocrine Pathology by Dr. Yabut  some pts have no SSX, the d/o is detected incidentally during routine thyroid testing  Laboratory: during periods of thyrotoxicosis  elevated T4andT3, depressed TSH levels Riedel Thyroiditis  less common form of thyroiditis  rare idiopathic d/o  characterized by extensive fibrosis involving the thyroid & contiguous neck structures  presence of a hard & fixed thyroid mass clinically simulates a thyroid Ca  may be assoc w/ idiopathic fibrosis in other sites of the body such as the retroperitonium  presence of circulating antithyroid antibodies in most pts suggests an autoimmune etiology Palpation Thyroiditis  caused by vigourous clinical palpation of the thyroid gland  results in multifocal follicular disruption assoc w/ chronic inflammatory cells & occasional giant cell formation  abnormalities of thyroid fnc are not present MORPHOLOGY  except for possible mild enlargement, thyroid appears normal on gross inspection  Histologic: lymphocytic infiltration w/ hyperplastic germinal centers w/in the thyroid parenchyma & patch disruption & collapse of thyroid follicles  fibrosis & Hurthle cell metaplasia not commonly seen GRAVES DISEASE  in 1853, Graves reported observations of a dse characterized by violent and long continued palpitations in females assoc w/ enlargement of thyroid gland  most common cause of endogenous hyperthyroidism  TRIAD OF CLINICAL FINDINGS:

 HYPERTHYROIDISM – hyperfunctional, diffuse enlargement of thyroid

 INFILTRATIVE OPHTHALMOPATHY – w/ resultant exophthalmos

 Localized infiltrative DERMOPATHY – also called

PRETIBIAL MYXEDEMA  has peak incidence b/n 20-40 yrs, women 7x more affected than men  genetic susceptibility to Graves assoc w/ presence of major histocompatibility haplotypes, specifically HLAB8 & HLA-DR3  polymorphisms in the cytotoxic T-lymphocyteassociated-4 (CTLA-4) gene are also linked  HLA proteins – critical component of antigen presentation to T cells  CTLA-4 – inhibitory receptor that prevents T-cell responses to self-antigens  genomewide linkage analyses: additional susceptiblility loci localized to chromosome 6p (also linkes w/ Hashimoto) & chromosome 20q

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PATHOGENESIS  autoimmune d/o in w/c a variety of antibodies may be present in the serum  include antibodies to TSH receptor, thyroid peroxisomes, and thyroglobulin  AUTOANTIBODIES TO TSH RECEPTOR – central to disease pathogenesis  specific effects of antibodies depend on w/c TSH receptor epitope they are directed against: Thyroid-Stimulating Immunoglobulin (TSI)  serum from Graves pts conatin long-acting thyroid stimulator (LATS) – long-acting bcoz it stimulate thyroid fnc more slowly than TSH  LATS proved to be an IgG antibody that binds to TSH receptor & mimics the axn of TSH  stimulating adenyl cyclase   release of thyroid hormones  all pts have detectable levels of this autoantibody  TSI is relatively specific for Graves Thyroid growth-stimulating immunoglobulins (TGI)  also directed against TSH receptor  have been implicated in the proliferation of thyroid follicular epithelium TSH-binding inhibitor immunoglobulins (TBII)  prevent TSH from binding normally to its receptor on thyroid epithelial cells  some forms of TBII mimic the axn of TSH  stimulation of thyroid epithelial cell activity  some may also inhibit thyroid cell function  possible coexistence of both stimulating & inhibitory immunoglobulins in the serum  explains why some pts spontaneously develop episodes of hypothyroidism  trigger for initiation of autoimmune reaction in Graves remains uncertain, but most likely due to breakdown in helper T-cell tolerance, resulting in prod’n of anti-TSH autoantibodies Graves Ophthalmopathy  T-cell mediated autoimmune phenomenon plays a role in the dev’t of infiltrative ophthalmopathy  volume of retro-orbital connective tissues & extraocular muscles is  owing to several causes:  marked infiltration of retro-orbital space by mononuclear cells (Tcells)  inflammatory edema & swelling of extraocular muscles  accumulation of extracellular matrix components (specifically hydrophilic glycosaminoglycans GAGs such as hyaluronic aicd & chondroitin sulfate)   numbers of adipocytes (FATTY INFILTRATION)  these changes displace the eyeball forward & can interfere w/ func of extraocular muscles  Orbital Preadipocyte Fibroblasts – express the TSH receptor thus becoming targets of autoimmune attack  T cells reactive against these fibroblasts secrete cytokines  stimulate fibroblast proliferation & synthesis of extracellular matrix proteins (GAGs) & 

Pathology – Endocrine Pathology by Dr. Yabut surface TSH receptor expression  immune response perpetuation  progressive infiltration of retro-orbital space & ophthalmopathy  autoimmune d/o of the thyroid span a continuum; Graves (hyperfunction of thyroid) to Hashimoto (hypothyroidism)  there are families w/ coexistence of both  there is histologic overlap b/n autoimmune thyroid d/o (prominent intrathyroidal lymphoid cell infiltrates w/ germinal center formation)  in both d/o, frequency of other autoimmune dse (SLE, pernicious anemia, type 1 diabetes, Addison dse) is increased CLINICAL COURSE  include changes referable to thyrotoxicosis as well as those uniquely w/ Graves (diffuse hyperplasia of the thyroid, ophthalmopathy, dermopathy)  diffuse enlargement of thyroid is present in all cases of Graves  thyroid enlargement may be accompanied by flow of blood thru the hyperactive gland  producing an audible bruit  sympathetic overactivity  wide, staring gaze & lid lag  ophthalmopathy results in abnormal protrusion of the eyeball (Exophthalmos)  extraocular muscles are often weak  exophthalmos may persist or progress despite tx of thyrotoxicosis  may result to corneal injury  Infiltrative Dermopathy or Pretibial Myxedema – most common in skin overlying the shins; presents as scaly thickening & induration of the skin (present only in minority)  skin lesions may be pigmented papules or nodules & often have an orange peel texture  Laboratory: Elevated free T4&T3; Depressed TSH  Radioactive iodine uptake is  - due to ongoing stimulation of thyroid follicles by TSI  diffuse uptake of iodine  Tx include:  decreasing the symptoms of hyperthyroidism that are induced by  β-adrenergic tone (e.g tachycardia, palpitations, tremulousness, anxiety)  measures aimed at decreasing thyroid hormone synthesis such administration of Thionamides (e.g. propylthiouracil), radioiodine ablation, surgical intervention MORPHOLOGY

 thyroid gland usually symmetrically enlarged due to

diffuse hypertrophy & hyperplasia of thyroid follicular epith cells  gland usually smooth & soft, capsule is intact  in weight to over 80gm  not uncommon  parenchyma has soft, meaty appearance resembling normal muscles  HISTOLOGIC: dominant feature is TOO MANY CELLS  follicular epith cells in untreated cases are tall & crowded  crowding often results to formation of small papillae  project into follicular lumen & encroach on the colloid sometimes filling the follicles

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 papillae lack fibrovascular cores  colloid w/in lumen is pale, w/ scalloped margins  lymphoid infiltrates (T cells, w/ fewer Bcells & mature plasma cells) – present throughout the interstitium  germinal centers are common  preoperative therapy – alters morphology of the thyroid  preoperative administration of iodine  involution of epithelium & accumulation of colloid by blocking thryoglobulin secretion  Tx w/ PTU exaggerates the epithelial hypertrophy & hyperplasia by stimulating TSH secretion  Changes in extrathyroidal tissue include:  generalized lymphoid hyperplasia  heart may be hypertrophied  ischemic changes may be present (esp in pts w/ CAD)  in pts w/ ophthalmopathy – tissues of orbit are edematous due to the presence of hydrophilic mucopolysaccharides; plus infiltration by lymphocytes & fibrosis  dermopathy characterized by thickening of the dermis due to deposition of GAGs & lymphocyte infiltration DIFFUSE and MULTINODULAR GOITERS  GOITER – enlargement of the thyroid; most common manifestation of throid disease  reflect impaired synthesis of thyroid hormone most often caused by dietary iodine insufficiency  impaired thyroid hormone synthesis  compensatory rise in serum TSH  hypertrophy & hyperplasia of thyroid follicular cells  gross enlargement of thyroid gland  compensatory increase in functional mass is able to overcome hormone deficiency  ensures EUTHYROID metabolic state  if underlying d/o is sufficiently severe (e.g. congenital biosynthetic defect or endemic iodine deficiency), compensatory responses may be inadequate  Goitrous Hyperthyroidism  degree of thyroid enlargement is proportional to level & duration of thyroid hormone deficiency DIFFUSE NONTOXIC (SIMPLE) GOITER  diffusely involves the entire gland w/o producing nodularity  Colloid Goiter – bcoz the enlarged follicles are filled w/ colloid  occurs in both endemic and sporadic distribution ENDEMIC GOITER  in areas where soil, water, & food have low iodine levels  when goiters are present in more than 10% of the pop’n  lack of iodine  synthesis of thyroid hormone & compensatory  in TSH  follicular cell hypertrophy & hyperplasia & goitrous enlargement  Goitorgens – substance that interfere w/ thyroid hormone synthesis (e.g excessive calcium & vegetables belonging to Brassica and Crucifera

Pathology – Endocrine Pathology by Dr. Yabut families [cabbage, cauliflower, Brussels sprouts, turnips, cassava])  cassava contains THIOCYANATE w/c inhibits iodide transport w/in the thyroid SPORADIC GOITER  occurs less frequently  female preponderance & peak incidence at puberty or in young adult  Causes:  goitrogens  hereditary enzymatic defects that interfere w/ thyroid hormone synthesis  all are transmitted as Autosomal-recessive conditions  in most cases, cause of sporadic goiter is not apparent CLINICAL COURSE  pts are clinically euthyroid  clinical manifestations are primarily related to mass effects from the enlarged thyroid gland  T4&T3 levels are normal  TSH is usually elevated or at the upper range of normal  in children, dyshormogenetic goiter, caused by congenital biosynthetic defect, may induce cretinism MORPHOLOGY  2 Phases identified  Hyperplastic Phase  thyroid gland is diffusely & symmetrically enlarged  increase is usually modest; gland rarely exceeds 100-150gm  follicles are lined by crowded columnar cells w/c may pile up & form projections similar in Graves  accumulation is not uniform; some follicles are hugely distended while some remain small  Phase of Colloid Involution  if dietary iodine  or demand for thyroid hormone   stimulated follicular epith involutes to form an enlarged, colloid-rich gland (Colloid Goiter)  cut surface of thyroid is usually brown, somewhat glassy, translucent  follicular epithelium is flattened & cuboidal; colloid is abundant during periods of involution MULTINODULAR GOITER  irregular enlargement of the thyroid due to recurrent episodes of hyperplasia & involution  virtually, all long-standing simple goiters convert into multinodular goiters  may be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter)  produce the most extreme thyroid enlargements & are more frequently mistaken for neoplastic involvement than any other form of thyroid disease  occur in both endemic & sporadic form  may arise bcoz of variations among follicular cells in response to external stimuli such as trophic hormones

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 cells w/in follicles w/ growth advantage perhaps bcoz of intrinsic genetic abnormalities  develop into clones of proliferating cells  formation of nodule w/ autonomous growth  both polyclonal & monoclonal nodules coexist w/in the same multinodular goiter  mutations in proteins of the TSH-signaling pathway that lead to constitutive activation of this pathway have been identified in a subset of autonomous thyroid nodules  uneven follicular hyperplasia  generation of new follicles, uneven accumulation of colloid, tensions, stresses  rupture of follicles & vessels  hemorrhages, scarring, calcification  scarring adds to tensions  nodularity  stromal framework may enclose areas of expanded parenchyma  nodularity CLINICAL COURSE  dominant clinical features: caused by Mass Effects of the enlarged gland  large neck mass  airway obstruction, dysphagia, compression of large vessels in the neck & upper thorax  most pts are euthyroid  PLUMMER SYNDROME - in a minority of pts, a hyperfunctioning nodule may develop w/in a longstanding goiter  hyperthyroidism (toxic multinodular goiter) ! not accompanied by infiltrative ophthalmopathy & dermopathy  may be assoc w/ clinical evidence of hypothyroidism  radioiodine uptake is uneven (varied levels of activity)  hyperfunctioning nodules concentrate radioiodine and appear “hot”  goiters are also of clinical significance due to their ability to mask or to mimic neoplastic diseases arising in the thyroid MORPHOLOGY  multilobulated, asymmetrically enlarged glands  can reach up to 2000gm  pattern of enlargement is quite unpredictable & may involve one lobe far more than the other  lateral pressure on midline structures such as trachea & esophagus  INTRATHORACIC or PLUNGING GOITER – in some cases, goiter grows behind the sternum & clavicles  occasionally, most of it is hidden behind the trachea & esophagus  in some cases, one nodule may stand out as to appear like a solitary nodule  Cut section: irregular nodules contain variable amts of brown, gelatinous colloid  regressive changes occur frequently, particularly in older lesions; include areas of hemorrhage, fibrosis, calcification, cystic changes  Microscopic: colloid-rich follicles lined by flattened, inactive epithelium & areas of follicular epithelial

Pathology – Endocrine Pathology by Dr. Yabut hypertrophy & hyperplasia accompanied by degenerative changes NEOPLASMS of the THYROID  solitary thyroid nodule is a palpably discrete swelling w/in an otherwise apparently normal thyroid gland  single nodules are abt 4x more common in women  incidence of thyroid nodule increases throughout life  possibility of neoplastic dse is of major concern in pts w/ thyroid nodules  majority of solitary nodules prove to be localized, nonneoplastic conditions (e.g. nodular hyperplasia, simple cysts, or foci of thyroiditis) or benign neoplasms such as follicular adenomas  benign neoplasms : thyroid Ca ratio is 10:1  Clinical criteria for determining the nature of a thyroid nodule:  Solitary Nodules – more likely to be neoplastic than multiple nodules  Nodules in younger pts – more likely neoplastic than those in older pts  Nodules in males – more likely to be neoplastic than in females  A history of radiation treatment to the head & neck rgn is assoc w/ an increased incidence of thyroid malignancy  Nodules that take up radioactive iodine in imaging studies (hot nodules) – more likely to be benign than malignant  morphologic evaluation of a given thyroid nodule thru FNAB & histologic study of surgically resected parenchyma  provides the most definitive info about its nature ADENOMAS  typically discrete, solitary masses  derived from follicular epithelium  follicular adenomas  various terms have been proposed on the Classification of Adenomas based on degree of follicle formation and Colloid content:  Simple Colloid Adenomas (macrofollicular adenomas) – common form; resemble normal thyroid tissue  Fetal or Microfollicular, Embryonal or Trabecular – recapitulate stages in the embryogenesis of the normal thyroid  mixed patterns are common; most of these benign tumors are nonfunctional  follicular adenomas can be difficult to distinguish from dominant nodules of follicular hyperplasia or follicular Ca  although majority are nonfunctional, a small portion produce thyroid hormones & cause clinically apparent thyrotoxicosis  TOXIC ADENOMAS – functional adenomas that produce thyroid hormone independent of TSH & is an example of Thyroid Autonomy (same as toxic multinodular goiters) PATHOGENESIS

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 TSH receptor signaling pathway impt in pathogenesis of toxic adenomas  “gain of function” or activating somatic mutations in 1 of 2 components of this signaling system (most often TSH receptor or α-subunit of Gs )  chronic overprod’n of cAMP  generates cells w/ growth advantage  clonal expansion of follicular epith cells that can autonomously produce thyroid hormone  symptoms of thyroid excess CLINICAL FEATURES

 many thyroid adenomas present as unilateral painless mass often discovered during routine P.E.  larger masses produce local symptoms such as difficulty in swallowing  most adenomas take up less radioactive iodine than normal thyroid parenchyma  on radionuclide scanning: adenomas are “cold” nodules  up to 10% of “cold” nodules eventually prove to be malignant  malignancy is rare in “hot” nodules  in minority of cases, adenomas may be hyperfunctional, producing SSx of hyperthyroidism (toxic adenoma)  on radionuclide imaging: hyperfunctioning adenomas are “hot” nodules compared to paranodular thyroid tissue w/c is deprived of thyrotropin stimulation  hot adenomas occasionally have TSH dependence & may be induced to regress by administration of thyroid hormones w/c suppress TSH secretion  Ultrasonography & FNAB – for preoperative evaluation of suspected adenomas  THE DEFINITIVE DX OF ADENOMAS CAN BE MADE ONLY AFTER CAREFUL HISTOLOGIC EXAM OF RESECTED SPECIMEN  suspected adenomas are removed to exclude malignancy  thyroid adenomas, including atypical adenomas have excellent prognosis & do not recur or metastasize  abt 20% of follicular adenomas have point mutations in the RAS family of oncogenes w/c are also identified in 30-40% of follicular Ca  possiblity that some adenomas may progress to Ca MORPHOLOGY  solitary, spherical, encapsulated lesion, welldemarcated  ave. of abt 3cm (some are smaller or grow up to 10cm)  on resected specimens: adenoma bulges from cut surface & compress adjacent thyroid  gray-white to red-brown, depending on the cellularity of the adenoma & its colloid content  neoplastic cells are demarcated from adjacent parenchyma by a well-defined, intact capsule  These features are impt in distinguishing adenoma from Multinodular Goiters w/c have multiple nodules, less compression of thyroid, & lack of well-formed capsule

Pathology – Endocrine Pathology by Dr. Yabut  Areas of hemorrhage, fibrosis, calcifications, & cystic changes similar to those in multinodular goiters are COMMON in follicular adenomas (esp in larger lesions)  Microscopically: cells often form uniform-appearing follicles that contain colloid  follicular growth pattern is distinct from the adjacent non-neoplastic thyroid UNLIKE in multinodular goiters wherein growth patterns of maybe similar  epithelial cells of follicular adenomas reveal little variation in cell & nuclear morphology  mitotic figures are rare; mitotic activity needs careful exam to exclude follicular Ca  papillary change is not typical; if extensive, may raise suspicion of an Encapsulated Papillary Ca  OXYPHIL or HURTHLE CELL CHANGE - occasionally, neoplastic cells acquire bright eosinophilic granular cytoplasm  HURTHLE CELL ADENOMA – clinical presentation & behavior of a follicular adenoma w/ oxyphilia  Other variants of Follicular adenomas: CLEAR CELL FOLLICULAR ADENOMA (extensive clear cell change of cytoplasm) & SIGNET-RING CELL FOLLICULAR ADENOMA (adenomas w/ signet-ring features)  ENDOCRINE ATYPIA - similar to endocrine tumors @ other anatomic sites, benign follicular adenomas may occasionally exhibit focal nuclear pleomorphism, atypia, prominent nucleoli; doesn’t constitute a feature of malignancy  ATYPICAL FOLLICULAR ADENOMAS – adenomas that can demonstrate cellularity, more extensive variation in cellular size & nuclear morphology, & even mitotic activity  HALLMARK OF ALL FOLLICULAR ADENOMAS: PRESENCE OF AN INTACT, WELL-FORMED CAPSULE ENCIRCLING THE TUMOR OTHER BENIGN TUMORS  solitary nodules of the thyroid gland may also prove to be cysts  great preponderance represent cystic degeneration of a follicular adenoma while the remainder probably arise in multinodular goiters  often filled w/ brown, turbid fluid containing blood, hemosiderin pigment, & cell debris  additional benign rarities include dermoid cysts, lipomas, hemangiomas, teratomas (seen mainly in infants) CARCINOMAS  mostly occur in adults, although papillary Ca may present in childhood  female preponderance noted among pts who develop thyroid Ca in early & middle adult yrs  related to expression of estrogen receptors on neoplastic thyroid epithelium  cases presenting in childhoos\d & late adulthood are equally distributed among males & females  most thyroid Ca are well-differentiated lesions  Major Subtypes & relative frequencies: PAPILLARY Ca: 75-85% of cases FOLLICULAR Ca: 10-20% of cases

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MEDULLARY Ca: 5% of cases ANAPLASTIC Ca: <5% of cases  most thyroid Ca are derived from the follicular epithelium EXCEPT FOR MEDULLARY Ca w/c is derived from the parafollicular or C cells PATHOGENESIS - there are several factors, genetic & environmental, implicated in the pathogenesis of thyroid Ca GENETIC FACTORS  impt in both familial & nonfamilial (sporadic) forms of thyroid Ca  Familial medullary Ca – accts for most inherited cases of thyroid Ca  Familial Nonmedullary thyroid Ca (papillary & follicular variants) – very rare  distinct genes are ivolved in the histologic variants of thyroid Ca FOLLICULAR THYROID Ca (FTC)  approx ½ of FTC harbor mutations in the RAS family of oncogenes (HRAS, NRAS, & KRAS)  NRAS mutations are most common  recently, unique translocation has been described b/n PAX8 (paired homeobox gene impt in thyroid dev’t) & PPARγ1 (peroxisome proliferators-activated receptor γ1; nuclear hormone receptor implicated in terminal differentitaiton of cells)  PAX8- PPARγ1 fusion is present in approx 1/3 of FTC, specifically those Ca w/ t(2;3)(q13;p25) translocation  permits juxtaposition of portions of both genes  follicular Ca appear to arise by at least 2 distinct & virtually nonoverlapping molecular pathways: tumors carry either a RAS mutation or a PAX8-PPARγ1  both genetic abnormalities rarely present in same case PAPILLARY THYROID Ca (PTC)  appear to arise by multiple distinct, nonoverlapping molecular pathways 1) one involves arrangements of tyrosine kinase receptors RET or NTRK1 (neurotrophic tyrosine kinase receptor 1) 2) another involves activating mutations in the BRAF oncogene 3) 3rd pathway involves RAS mutations (10-20% of PTC)  suggests relation w/ follicular adenomas

 RET – located on chromosome 10q11  NTRK – located on chromosome 1q21  both belong to the family of receptor tyrosine kinases

that transduce extracellular signals fro cell growth & differentiation & exert many of their downstream effects thru MAP kinase signaling pathway  neither receptor is normally expressed on the surface of thyroid follicular cells  either a paracentric inversion of chromosome 10 or a reciprocal translocation b/n chromosomes 10 & 17 places tyrosine kinase domain of RET under the

Pathology – Endocrine Pathology by Dr. Yabut transcriptional control of active genes on these chromosomes  ret/PTC (ret/papillary thyroid Ca) – novel fusion genes present in approx 1/5 of PTC  frequency of ret/PTC rearrangements is  in papillary Ca arising in children w/ radiation exposure  paracentric inversions or translocations of NTRK1 that activate its tyrosine kinase domain  present in 5-10% of PTC  1/3 to ½ of PTC harbor mutation in the BRAF gene, w/c encodes a signaling intermediary in the MAP kinase pathway  chromosomal rearrangement of the RET & NTRK1 genes & mutations of BRAF have redundant effects on thyroid epith  PTC demonstrate only one of these abnormalities MEDULLARY THYROID Ca (MTC)  arise form C cells in the thyroid  familial MTC occur in multiple endocrine neoplasia type 2 (MEN-2)  assoc w/ germ-line RET protooncogene mutations that affect residues in the cysteine-rich extracellular or intracellular tyrosine kinase domains  constitutive activation of the receptor  RET mutations detectable in approx 95% of families w/ MEN-2  remaining few cases, mutations may arise in hard-todetect promoter sequences or intronic sites  RET mutations are also seen in nonfamilial (sporadic) MTC  no ret/PTC translocations ANAPLASTIC Ca  highly aggressive & lethal tumors  can arise de novo or by “dedifferentiation” of a welldifferentiated papillary or follicular Ca  inactivating point mutations in the p53 tumor suppressor gene are common (rare in welldifferentiated thyroid Ca) ENVIRONMENTAL FACTORS

 EXPOSURE TO IONIZING RADIATION – major risk

factor predisposing to thyroid Ca particularly in the 1st 2 decades  in the past, radiation therapy is used for tx of head & neck lesions in infants & children including reactive tonsillar enlargement, acen, tinea capitis  9% developed thyroid malignancies several decades postexposure  importance of radiation as major risk was highlighted due to  in incidence of PTC in children in Marshall Islands after atomic bomb testing  Long-standing multinodular goiter has been suggested as a predisposing factor in some cases since iodinedeficiency related endemic goiter have higher prevalence of follicular Ca  no conclusive evidence to relate thyroiditis w/ increased risk of thyroid epith Ca

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PAPILLARY CARCINOMA  most common form of thyroid cancer  occur at any age but most often in 20s-40s  acct for majority of thyroid Ca assoc w/ previous exposure to ionizing radiation CLINICAL COURSE  present as asymptomatic thyroid nodules  first manifestation may be a mass in a cervical lymph node  presence of isolated cervical nodal metastases does not appear influence the generally good prognosis  the carcinoma, usually a single nodule, moves freely during swallowing & is not distinguishable from a benign nodule  hoarseness, dysphagia, cough, or dyspnea  suggests advanced disease  in minority of cases, hematogenous metastases are present at time of Dx, usually in the lung  radionuclide scanning & FNAB – employed to separate benign from malignant thyroid nodules  papillary lesions are “cold” masses on scintiscans  FNAB – due to improvements in cytologic analysis, this became a reliable test for distinguishing benign from malignant nodules  nuclear features often nicely demonstrated in aspirated specimens  have excellent prognosis, w/ 10-yr survival rate in excess of 95%  5%-20% have local or regional recurrences  10%-15% have distant metastases  prognosis depends on several factors: age (less favorable in pts older than 40), presence of extrathyroidal extension, and presence of distant metastases (stage) MORPHOLOGY  solitary or multifocal lesions  some may be well-circumscribed & encapsulated  some may infiltrate adjacent parenchyma w/ ill-defined margins  lesions may contain areas of fibrosis & calcification & are often cystic  cut surface may appear granular & sometimes contain grossly discernible papillary foci  definitive dx can be made only after microscopic examination CHARACTERISTIC HALLMARKS of PAPILLARY NEOPLASMS

a) papillary Ca can contain branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epith cells  in most neoplasms  epithelium covering the papillae consists of well-differentiated, uniform, orderly, cuboidal cells or;  may be w/ fairly anaplastic epith showing considerable variation in cell & nuclear morphology  papillae of papillary Ca differ from those seen in areas of hyperplasia  neoplastic papillae are more complex & have dense fibrovascular cores

Pathology – Endocrine Pathology by Dr. Yabut b) nuclei of papillary Ca chromatin finely dispersed chromatin w/c imparts an optically clear or empty appearance  ground glass or Orphan Annie eye

 “Pseudo-inclusions” or Intranuclear inclusions  appearance of the invaginations of the cytoplasm in x.s.  Dx of papillary Ca is based on these nuclear features even in the absence of papillary architecture c) PSAMMOMA BODIES  concentrically calcified structures often present w/in the lesion, usually w/in the cores of papillae; strong indication of a Papillary Ca  almost never found in follicular & medullary Ca  whenever a psammoma body is found w/in a lymph node or perithyroidal tissues  a hidden papillary Ca must be considered d) - foci of lymphatic invasion by tumor are often present; - involvement of blood vessels is relatively uncommon particularly in smaller lesions; - Metastases to adjacent cervical lymph nodes are estimated to occur in ½ of the cases Variant Forms of Papillary Ca a) ENCAPSULATED VARIANT  constitutes abt 10% of all papillary neoplasms  usually confined to the thyroid  well encapsulated, rarely presents w/ vascular or lymph node dissemination  can be easily confused w/ benign adenoma  has excellent prognosis b) FOLLICULAR VARIANT  has characteristic nuclei of Papillary Ca but has an almost totally follicular architecture  may be encapsulated, psammoma bodies may be seen  still behave biologically as usual papillary Ca as long as they meet the criteria for Dx of papillary Ca  True Follicular Ca – lacks these nuclear features, frequently demonstrates capsular & vascular invasion, has less favorable prognosis c) TALL CELL VARIANT  marked by tall comunar cells w/ intensely eosinophilic cytoplasm lining the papillary structures  cells are at least 2x as tall as they are wide  tumors tend to occur in older people & are usually large w/ prominent vascular invasion, extrathyroidal extension, & cervical & distant metastases  recently demonstrated that more than ½ harbor a ret/PTC translocation potential than the ret/PTC observed in usual papillary thyroid Ca  presence of this genetic abnormality might result in more aggressive behavior d) DIFFUSE SCLEROSING VARIANT  unusual variant  occurs in younger individuals including children  tumors do not present w/ a mass but rather w/ a BILATERAL GOITER

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 characteristic “gritty” sensation to cut surface of

the lesion due to the presence of abundant psammoma bodies  prominent papillary growth pattern, intermixed w/ solid areas containing nests of squamous cells (Squamous Morules)  neoplastic cells exhibit classic nuclear features of a papillary neoplasm  extensive, diffuse fibrosis throughout the thyroid often assoc w/ prominent lymphocytic infiltrate, simulating Hashimoto  neoplastic cells have peculiar propensity to invade intrathyroidal lymphatic channels  nodal metastases are present in almost all cases e) HYALINIZING TRABECULAR TUMORS  a grp that includes both adenomas & Ca  recently been considered as a variant based on the presence of ret/PTC gene rearrangement in 30%60% of these tumors  “organoid” growth pattern w/ nests & trabeculae of elongated tumor cells w/in a fibrovascular stroma  at first glance, may resemble an extra-adrenal paraganglioma  both intra- & extracellular hyalinization are prominent & confer a pink hue on the tumor on LPO  nuclear features resemble those seen in classic papillary Ca & psammoma bodies may be present  well-encapsulated (Ca demonstrate capsular &/or vascular invasion) FOLLICULAR CARCINOMA

 2nd most common form; 10%-20% of all thyroid Ca  tend to present in women & at an older age than papillary Ca; peak incidence in 40s-50s  incidence is  in areas of dietary iodine deficiency  suggests nodular goiter may predispose to the dev’t of the neoplasm  high frequency of RAS mutations in follicular adenomas & Ca suggests that the 2 may be related tumors CLINICAL COURSE  present as slowly enlarging painless nodules  most frequently “cold” nodules; in some rare cases, better-differentiated lesions may be hyperfunctional, take up radioactive iodine & appear “warm” on scintiscan  have little propensity for invading lymphatics  regional lymph nodes are rarely involved  vascular invasion is common w/ spread to the bone, lungs, liver, & elsewhere  prognosis is largely dependent on the extent of invasion & stage at presentation  widely invasive follicular Ca not infrequently develop metastases; up to ½ succumb to their dse in 10 yrs in contrast to minimally invasive follicular Ca w/c has a 10yr survival rate greater than 90%  most are treated w/ Total Thyroidectomy followed by administration of radioactive iodine 

Pathology – Endocrine Pathology by Dr. Yabut Rationale: metastases are likely to take up the radioactive element w/c can be used to identify & ablate such lesions  pts are usually treated w/ thyroid hormone after surgery to suppress endogenous TSH bcoz any residual follicular Ca may respond to TSH stimulation MORPHOLOGY  single nodules that may be well-circumscribed or widely infiltrative  sharply demarcated lesions may be difficult to distinguish from follicular adenoma by gross exam  larger lesions may penetrate the capsule & infiltrate well beyond the thyroid capsule into the adjacent neck  gray to tan to pink, & on occasion, somewhat translucent when large, colloid-filled follicles are present  central fibrosis & foci of calcification (degenerative changes) are sometimes present  Microscopically: composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid  in other cases, follicular differentiation may be less apparent; nests or sheets of cells w/o colloid may be present  occasional tumors are dominated by Hurthle cells (cells w/ abundant granular, eosinophilic cytoplasm)  nuclei lack the features typical of papillary Ca  psammoma bodies are not present Note: absence of these details bcoz some papillary Ca may appear almost entirely follicular  follicular lesions w/ nuclear features typical of papillary Ca must be treated as papillary Ca  nuclear features are of little value in distinguishing follicular adenomas from minimally invasive follicular Ca Note: requires extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular &/or vascular invasion  criterion for vascular invasion is applicable only to capsular vessels & vascular spaces beyond the capsule  presence of tumor plugs w/in intratumoral blood vessels  little prognostic significance  lymphatic spread is uncommon  extensive invasion of adjacent thyroid parenchyma or extrathyroidal tissues  dx of Ca in widely invasive follicular Ca  Histologic: have a greater proportion of solid or trabecular growth pattern, less evidence of follicular differentiation, &  mitotic activity MEDULLARY CARCINOMA

 neuroendocrine neoplasms derived from C cells of the thyroid

 cells of medullary Ca secrete CALCITONIN (same as normal C cells); its measurement impt in dx & postop follow-up of pts  in some instances, tumor cells elaborate other polypeptide hormones such as somatostatin, serotonin, & vasoactive intestinal peptide (VIP)

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 tumors arise sporadically in abt 80% of cases  remaining occurs in the setting of MEN syndrome 2A or 2B or as familial tumors w/o an assoc MEN syndrome (FMTC)  cases assoc w/ MEN-2 occur in younger pts & may even arise during childhood  in contrast, sporadic medullary Ca & FMTC  lesions of adulthood (peak incidence in 40s-50s) CLINICAL COURSE

 sporadic cases most often present as a mass in the neck, sometimes assoc w/ local effects such as dysphagia, or hoarseness  in some, initial manifestations are those of paraneoplastic syndrome  caused by secretion of a peptide hormone (e.g. diarrhea owing to VIP secretion)  hypocalcemia not a prominent feature despite presence of raised calcitonin levels  for early detection of tumors in familial cases – screening relatives for elevated calcitonin or RET mutations  all mEN-2 kindred carrying RET mutations  given prophylactic thyroidectomy to preclude dev’t of medullary Ca, the major risk factor for poor outcomes in these families  sometimes, only histo finding in resected thyroid of asymptomatic carriers is the presence of C cell hyperplasia or small (<1cm) “micromedullary” Ca  recent studies show specific RET mutations correlate w/ aggressiveness of medullary Ca & propensity of MEN-2 pts to develop other coincident endocrine tumors MORPHOLOGY  arise as solitary nodule or multiple lesions involving both lobes of the thyroid  sporadic neoplasms tend to originate in one lobe  bilaterality & multicentricity – common in familial cases  larger lesions often contain areas of necrosis & hemorrhage & may extend thru the capsule of the thyroid  tumor tissue is firm, pale gray to tan, & infiltrative  Microscopically: composed of polygonal to spindleshaped cells w/c may form nests, trabeculae, & even follicles  small, more anaplastic cells are present in some tumors & may be the predominant cell type  Acellular Amyloid Deposits – derived from altered calcitonin molecules; present in the adjacent stroma in many cases  calcitonin is readily demonstrable w/in the cytoplasm of tumor cells as well as in stromal amyloid by immunohistochemical methods  EM: variable #s of membrane-bound electron-dense granules w/in the cytoplasm of neoplastic cells  Multicentric C-cell Hyperplasia – one peculiar feature of familial medullary Ca; present in surrounding thyroid parenchyma (usually absent in sporadic lesions)  precise criteria for defining C cell hyperplasia not established so;

Pathology – Endocrine Pathology by Dr. Yabut  presence of multiple prominent clusters of C cells scattered throughout the parenchyma – raise specter of familial tumor  Foci of C-cell hyperplasia are believed to represent the precursor lesions form w/c medullary Ca arise ANAPLASTIC CARCINOMA  undifferentiated tumors of thyroid follicular epithelium  aggressive tumors; mortality rate: 100%  tumors acct for fewer than 5% of all thyroid Ca  mean age = 65 yrs  abt ½ of pts have a Hx of multinodular goiter  20% - have Hx of differentiated Ca  another 20%-30% have concurrent differentiated thyroid tumor, frequently a papillary Ca  these findings led to the proposal that: anaplastic Ca develops by dedifferentiation from more differentiated tumors as a result of one or more genetic changes including loss of p53 tumor suppressor gene CLINICAL COURSE  usually present as a rapidly enlarging bulky neck mass  in most cases, dse has already spread beyond the thyroid capsule into adjacent neck structures or has metastasized to the lungs at the time of presentation  Compression and Invasion Symptoms  dyspnea, dysphagia, hoarseness, cough  common  no effective therapy; dse is almost uniformly fatal  metastases to distant sites are common  in most cases, death occurs in less than 1 yr as a result of aggressive growth & compromise of vital structures in the neck MORPHOLOGY  composed of highly anaplastic cells w/c may take one of several histologic patterns: 1.large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells 2.spindle cells w/ sarcomatous appearance 3.mixed spindle & giant cells 4.small cells resembling those in SCC arising at other sites  unlikely that a true small cell Ca exists in the thyroid  significant # of these small cell tumors were proven to be medullary Ca or malignant lymphomas w/c may also occur in thyroid but have better prognosis  foci of papillary or follicular differentiation may be present in some tumors  suggest origin form better differentiated Ca CONGENITAL ANOMALIES THYROGLOSSAL DUCT OR CYST  most common clinically significant congenital anomaly  persistent sinus tract may remain as a vestigial remnant of the tubular dev’t of the thyroid  part of this tube  obliterated  leaves small segments  forms cysts  occur at any age & might not become evident until adulthood

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 mucinous, clear secretions may collect w/in these cysts to form either spherical masses or fusiform swellings, rarely over 2-3cm  present in the midline of the neck anterior to trachea  segments of duct & cysts that occur high in the neck  lined by stratified squamous epithelium (identical w/ covering of posterior tongue in the region of foramen cecum)  anomalies that occur in the lower neck more proximal to the thyroid are lined by epithelium resembling thyroidal acinar epithelium  subjacent to the lining epithelium there is an intense lymphocytic infiltrate  superimposed infection may convert these lesions into abscess cavities and rarely give rise to cancers

PARATHYROID GLANDS  derived from developing pharyngeal pouches that also give rise to the thymus  four glands normally lie in close proximity to the upper & lower poles of each thyroid lobe  but may also be found anywhere along the pathway of descent of pharyngeal pouches (carotid sheath, thymus, elsewhere in anterior mediastinum)  10% of individuals have only 2-3 glands  (in adult) yellow-brown, ovoid encapsulated nodule weighing approx 35-40mg  composed mostly of CHIEF CELLS  vary from light to dark pink w/ H&E depending on their GLYCOGEN content  polygonal, 12-20mm; have central, round, uniform nuclei  contain secretory granules of PTH  sometimes have water-clear appearance due to lakes of glycogen  OXYPHIL CELLS & Transitional Oxyphils  found throughout the normal parathyroid  either singly or in small clusters  slightly larger than chief cells  acidophilic cytoplasm  tightly packed w/ mitochondria  glycogen granules are also present  secretory granules are sparse or absent  (infancy&childhood) composed almost entirely of solid sheets of chief cells  amt of stromal fat increases up to age 25, max: 30% of gland then plateaus  precise proportion of fat determined largely by constitutional factors: obese individuals have more adipose tissue in their glands  LEVEL OF FREE (IONIZED) CALCIUM in the bloodstream – controls activity of the gland; rather than trophic hormones secreted by the hypothalamus & pituitary  levels of free calcium  stimulate synthesis & secretion of PTH  CIRCULATING PTH

Pathology – Endocrine Pathology by Dr. Yabut  84-amino acid linear polypeptide derived by sequential cleavage in the chief cell of a larger pre-pro form  biologic activity resides w/in 34 residues at the amino terminus  smaller nonfunctional fragments also circulate (lacks the critical amino-terminal domain); biologically inert, contains epitopes that react in certain radioimmunoassay for PTH  PTH RECEPTOR  7-transmembrane G-protein-coupled receptor binding of hormone  activation of stimulatory G-protein (Gs)  adenylate cyclase-mediated generation of cAMP this pathway assumes clinical significance when abnormalities of the Gs protein result in either hyperactivity or hypoactivity of the parathyroid gland METABOLIC FUNCTIONS OF PTH (in supporting serum calcium levels)

 activates osteoclasts  mobilization of calcium from bone

 increases renal tubular reabsorption of calcium  conservation of free calcium  increases conversion of Vit. D to its active dihyroxy from in the kidneys  increases urinary phosphate excretion  lowering serum phosphate levels  augments GI calcium absorption  net result of these activities   levels of free calcium  inhibits further PTH secretion in a classic feedback loop

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 prognosis is poor in pts w/ malignancy-assoc hypercalcemia since it most commonly occur in pts w/ advanced Ca  hypercalcemia of malignancy is due to  bone resorption & subsequent release of calcium  2 Major Mechanismsby w/c this can occur: OSTEOLYTIC METASTASES

metastatic tumor cells as well as stromal cells in the

vicinity of metastases release a variety of soluble mediators  induce local osteolysis by promoting differentiation of committed osteoclast precursors into mature cells recently, critical osteoclastogenic pathway has been discovered involves RANK (osteoblast cell-surface receptor; receptor activator of nuclear factor κB), its ligand RANKL, & Osteoprotegerin (a decoy receptor for RANKL) decoy receptor – soluble receptor that competes w/ the true receptor, in this case RANK, for binding the ligand w/c is RANKL RANKL – aka osteoclast differentiation factor; by binding w/ RANK it promotes all aspects of osteoclast fnc (proliferation, differentiation, fusion, & activation); it is secreted by tumor cells & peritumoral stromal cells in metstatic foci & cause osteolysis Osteoprotegerin – inhibits this pathway of osteoclastogenesis & has emerged as a possible therapeutic agent in Ca pts w/ hypercalcemia of malignancy PTH-RELATED PROTEIN  RELEASE OF PTHrP - most frequent cause of hypercalcemia in nometastatic solid tumors (particularly squamous cell Ca)  classically, PTHrP-induced hypercalcemia was known as “HUMORAL HYPERCALCEMIA of MALIGNANCY” to distinguish it from hypercalcemia arising from osteolytic metastases  PTHrP contributes to hypercalcemia of malignancy irrespective of the presence or absence of metastases

HYPERCALCEMIA  one of a number of changes induced by elevated levels of PTH  relatively common complication of malignancy, occurring both w/ solid tumors, such as lung, breast, head & neck, renal Ca & w/ hematologic malignancies such asmultiple myeloma  MALIGNANCY IS THE MOST COMMON CAUSE OF CLINICALLY APPARENT HYPERCALCEMIA  primary hyperthyroidism – more common cause of asymptomatic elevated blood calcium

 this protein is immunologically distinct from PTH yet similar enough to permit binding to identical receptors & simulation of 2nd messengers (notably cAMP)  accts for ability of PTHrP to induce most of actions of PTH including  in bone resorption & inhibition of proximal tubule phosphate transport PATHOLOGY  abnormalities include both hyper- & hypofunction  tumors usually come into attention bcoz of EXCESSIVE SECRETION OF PTH rather than mass effects HYPERPARATHYROIDISM

Pathology – Endocrine Pathology by Dr. Yabut  occurs in 2 major forms – primary & secondary;  less commonly, tertiary form  1st condition: represents autonomous, spontaneous overprod’n of PTH  latter 2 conditions typically occur as secondary phenomena in pts w/ chronic renal insufficiency PRIMARY HYPERPARATHYROIDISM  one of the most common endocrine d/o  impt cause of hypercalcemia  Frequency of various parathyroid lesions underlying the hyperfunction: Adenoma: 75-80% Primary Hyperplasia (diffuse or nodular) 10-15% Parathyroid Ca: less than 5%  usually a dse of adults  more common in women than in men (3:1)  in more than 95% of cases, this d/o is caused by Sporadic Parathyroid Adenomas or Sporadic Hyperplasia  familial syndromes are a distant second but provided unique insight in the pathogenesis of primary hyperparathyroidism GENETIC SYNDROMES ASSOCIATED w/ FAMILIAL PRIMARY HYPERPARATHYROIDISM a) MULTIPLE ENDOCRINE NEOPLASIA – 1 (MEN-1)  MEN1 gene on chromosome 11q13 – tumor suppressor gene inactivated in a variety of MEN-1related parathyroid lesions (incl: parathyroid adenomas & hyperplasia)  MEN1 mutations have also been described in sporadic parathyroid tumors b) MULTIPLE ENDOCRINE NEOPLASIA – 2 (MEN-2)  caused by activating mutations in the tyrosine kinase receptor RET, on chromosome 10q  primary hyperparathyroidism occurs as a component of MEN-2A c) FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH)  autosomal-dominant d/o  enhanced parathyroid function due to decreased sensitivity to extracellular calcium  mutations in parathyroid CASR (calcium sensing receptor) on chromosome 3q – primary cause for this d/o  pts w/ homozygous CASR mutations – severe hyperparathyroidism in neonatal period  CASR mutations not described in sporadic tumors

 most sporadic parathyroid adenomas are monoclonal  suggests they are true neoplastic outgrowths from a single abnormal progenitor cell  sporadic parathyroid hyperplasia is also monoclonal when assoc w/ a persistent stimulus for parathyroid growth (refractory secondary or tertiary parathyroidism) 2 Molecular Defects: a) PARATHYROID ADENOMA 1 (PRAD1)

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 PRAD1 encodes cyclin D1 (major regulator of cell cycle)  pericentromeric inversion on chromosome 11  relocation of PRAD1 protooncogene so it is positioned adjacent to the 5’ flanking region of the PTH gene (on 11p)  Consequence: regulatory element from PTH gene 5’ flanking sequence directs overexpression of cyclin D1 protein  force cells to proliferate  10-20% of adenomas have this clonal genetic defect  cyclin D1 is overexpressed in approx 40% of parathyroid adenomas  suggests other mechanisms that can lead to its activation b) MEN1  20-30% of parathyroid tumors not assoc w/ MEN-1 syndrome demonstrate mutations in both copies of MEN1 gene  spectrum of MEN1 mutations identical to that in familial parathyroid adenoma CLINICAL COURSE PRIMARY HYPERPARATHYROIDISM  presents in 1 of 2 general ways  it may be asymptomatic & be identified after a routine chemistry profile  patients may have the classic clinical manifestations of primary hyperparathyroidism Asymptomatic Hyperparathyroidism

 blood tests for unrelated conditions  serum calcium levels routinely assessed  early detection of clinically silent hyperparathyroidism  level of serum ionized calcium – most common manifestation of primary hyperparathyroidism  primary hyperparathyroidism – most common cause of asymptomatic hypercalcemia  malignancy – most common cause of clinically apparent hypercalcemia in adults (must be excluded by appropriate clinical & lab tests in pts w/ suspected hyperparathyroidism)  pts w/ 1º hyperparathyroidism – serum PTH levels are inappropriately elevated for the level of serum calcium; but in hypercalcemia, PTH levels are low to undetectable bcoz of nonparathyroid dses  in pts w/ hypercalcemia caused by PTHrP secretion by nonparathyroid tumors  radioimmunoassays specific for PTH & PTHrP can distinguish b/n the 2  Other lab alterations referable to PTH excess: hypophosphatemia & urinary excretion of both calcium & phosphate  secondary renal dse may lead to phosphate retention w/ normalization of serum phosphates Symptomatic Primary Hyperparathyroidism

 SSx of hyperparathyroidism reflect the combined effects of PTH secretion & hypercalcemia

 traditionally assoc w/ a constellation of symptoms

that included “painful bones, renal stones, abdominal groans, & psychic moans”

Pathology – Endocrine Pathology by Dr. Yabut Symptomatic Presentation w/ Diverse Clinical Manifestations Bone Disease - includes bone pain 2º to fractures of bones weakend by osteoporosis or osteitis fibrosa cystica Nephrolithiasis (renal stones) - occurs in 20% of newly diagnosed pts; w/ attendant pain & obstructive uropathy - chronic renal insufficiency & variety of abnormalities in renal func are found, including polyuria & 2º polydipsia Gastrointestinal disturbances - constipation, nausea, peptic ulcer, pancreatiits, gallstones CNS alterations - depression, lethargy, eventually seizures Neuromuscular abnormalities - complaints of weakness & fatigue Cardiac manifestations - aortic or mitral valve calcifications (or both)

 nephrolithiasis & bone dse  most directly related to hyperparathyroidism  fatigue, weakness, constipation – attributable to hypercalcemia  pathogenesis of other manifestations still poorly understood MORPHOLOGY  changes include those in the parathyroid glands, as well as other organs affected by elevated levels of calcium Parathyroid Adenomas  almost always solitary & may lie near the thyroid gland or in an ectopic site  ave: 0.5 – 5.0 gm  well-circumscribed, soft, tan to reddish-brown; invested by a delicate capsule  glands outside adenoma are usually normal in size or somewhat shrunken bcoz of feedback inhibition by elevation in serum calcium  Microscopically: predominance of fairly uniform, polygonal chief cells w/ small, centrall-placed nuclei  at least a few nests of larger cells containing oxyphil cells are present  Oxyphil Adenoma – uncommon type wherein oxyphils comprise the whole adenoma  Chief cells arranged in various patterns; follicles same as in thyroid are present in some cases  mitotic figures are rare  rim of compressed, nonneoplastic parathyroid tissue, generally separated by a fibrous capsule is often visible at the edge of the adenoma  Endocrine Atypia – bizarre & pleomorphic nuclei even w/in adenomas; not uncommon; should not be used for defining malignancy Primary Hyperplasia  may occur sporadically or as a component of MEN syndrome

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 frequent asymmetry w/ apparent sparing of 1 or 2 glands making the distinction b/n hyperplasia & adenoma difficult  combined wt ofall glands rarely exceeds 1.0gm & is often less  Microscopically: Chief Cell Hyperplasia – most common pattern w/c may involve the glands in diffuse or multinodular pattern  water-clear cell hyperplasia – less common  there are islands of oxyphils, poorly developed delicate fibrous strands may envelop the nodules  stromal fat is inconspicuous w/in the foci of hyperplasia Parathyroid Carcinomas  may be fairly circumscribed lesions that are difficult to distinguish from adenomas  or may be clearly invasive neoplasms  these tumors enlarge one parathyroid gland & consists of gray-white, irregular masses that sometimes exceed 10 gm  cells are usually uniform & resemble normal parathyroid cells  arrayed in nodular or trabecular patterns w/ a dense, fibrous capsule enclosing the mass  Diagnosis of Ca based on cytologic detail is UNRELIABLE, & invasion of surrounding tissues & metastasis are the only reliable criteria of malignancy  local recurrence occur in 1/3 of cases; more distant dissemination occurs in other 3rd Morphologic Changes in other organs Skeletal Changes  prominence of osteoclasts w/c erode bone matrix & mobilize calcium salts esp in metaphyses of long tubular bones  bone resorption is accompanied by osteoblastic activity & formation of new bone trabeculae  in many cases, resultant bone contains widely spaced, delicate trabeculae same as in osteoporosis  in more severe cases, cortex is grossly thinned, marrow contains increased amts of fibrous tissue accompanied by foci of hemorrhage & cyst formation  OSTEITIS FIBROSA CYSTICA  aggregates of osteoclasts, reactive giant cells, & hemorrhagic debris occasionally form masses that may be mistaken for neoplasms  BROWN TUMORS of HYPERPARATHYROIDISM Renal Lesions/ Changes

 PTH-induced hypercalcemia favors Nephrolithiasis (formation of urinary tract stones)  and also Nephrocalcinosis – calcification of renal interstitium & tubules  metastatic calcification secondary to hypercalcemia may also be seen in other sites such as stomach, lungs, myocardium, & blood vessels SECONDARY HYPERPARATHYROIDISM  caused by any condition assoc w/ chronic depression in the serum calcium level since low serum calcium leads to compensatory overactivity of the parathyroid glands

Pathology – Endocrine Pathology by Dr. Yabut  Renal Failure – by far the most common cause  other conditions that may cause this include: inadequate dietary intake of calcium, steatorrhea, vit. D deficiency  chronic renal insufficiency is assoc w/ phosphate excretion  hyperphosphatemia  elevated serum phosphate levels directly depress calcium levels  stimulate parathyroid gland activity  loss of renal substance reduces the availability of α-1hydroxylase necessary for the synthesis of the active form of vit D  intestinal absorption of calcium CLINICAL COURSE  usually dominated by those assoc w/ chronic renal failure  bone abnormalities (renal osteodystrophy) & other changes w/ PTH excess are less severe than those in 1º hyperparathyroidism  vascular calcification assoc w/ 2º hyperparathyroidism may occasionally result in significant ischemic damage to skin & other organs  CALCIPHYLAXIS  in a minority of pts, parathyroid activity may become autuonomous & excessive resulting to hypercalcemia  TERTIARY HYPERPARATHYROIDISM  parathryoidectomy may be necessary to control hyperparathyroidism in such pts MORPHOLOGY  glands are hyperplastic  degree of glandular enlargement is not necessarily symmetric  Microscopically: hyperplastic glands contain # of chief cells or water-clear cells in a diffuse or multinodular distribution  fat cells are   bone changes similar to those in primary hyperparathyroidism may also be present  metastatic calcification may be seen in many tissues including lungs, heart, stomach, & blood vessels

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- syndrome known as AUTOIMMUNE POLYENDOCRINE SYNDROME TYPE 1 (APS1); caused by mutations in the AUTOIMMUNE REGULATOR gene (AIRE) - syndrome typically presents in childhood w/ onset of candidicasis followed by hypoparathyroidism & then adrenal insufficiency during adolescence d) IDIOPATHIC HYPOPARATHYROIDISM - most likely represents an autoimmune dse w/ isolated atrophy of the glands - 60% of pts have autoantibodies against CASR (calcium-sensing receptor) in the parathyroids - antibody binding to receptor may prevent PTH release  Major Clinical manifestations of Hypoparathyroidism are referable to hypocalcemia & are related to the severity & chronicity of the hypocalcemia 

 Mental status changes: emotional instability,

HYPOPARATHYROIDISM  far less common than hyperparathyroidism



Possible Causes of Deficient PTH secretion a) SURGICALLY INDUCED HYPOPARATHYROIDISM - occurs w/ inadvertent removal of ALL parathyroid glands during thyroidectomy; excision of parathyroids mistaken as lymph nodes during radical neck dissection for some form of malignant dse; or removal of too large a proportion of parathyroid tissue in tx of 1º hyperparathyroidism b) CONGENITAL ABSENCE OF ALL GLANDS - certain developmental abnormalities such as Thymic Aplasia & Cardiac Defects (22q11.2 syndrome)



c) FAMILIAL HYPOPARATHYROIDISM - often assoc w/ chronic mucocutaneous candidiasis & primary adrenal insufficiency;

TETANY - hallmark of hypocalcemia - neuromuscular irritability resulting from serum ionized calcium concentration - findings can range from circumoral numbness or paresthesias (tingling) of the distal extremities & carpopedal spasm to life-threatening laryngospasm & generalized seizures - Classical findings on P.E. CHVOSTEK SIGN – elicited in subclinical dse by tapping along the course of the facial nerve w/c induces contractions of the eye muscles, mouth or nose TROUSSEAU SIGN – occluding the circulation to the forearm & hand by inflating a BP cuff about the arm for several minutes induces CARPAL SPASM , w/c disappears as soon as the cuff is deflated

 

anxiety, depression, confusional states, hallucinations, frank psychosis Intracranial manifestations: calcifications of the basal ganglia, parkinsonian-like mov’t d/o,  intracranial pressure w/ resultant papilledema Ocular disease: results in calcification of the lens leading to cataract formation Cardiovascular manifestations: conduction defect w/c produces characteristic prolongation of QT interval Dental abnormalities: dental hypoplasia, failure of eruption, defective enamel & root formation, abraded carious teeth

PSEUDOHYPOPARATHYROIDISM

 hypoparathyroidism occurs bcoz of END-ORGAN RESISTANCE TO THE ACTIONS OF PTH  serum PTH levels are normal or increased  2 Key Concepts in PTH Resistance

Pathology – Endocrine Pathology by Dr. Yabut

 G-proteins, principally Gs mediate the cellular

actions of PTH on bone & kidney  GNAS1 is a selectively imprinted gene w/ tissuespecific patterns of imprinting  in most cases, Gsα the product of GNAS1 is expressed from both alleles  in pituitary & kidney, GNAS1 is expressed only from maternally inherited chromosome, owing to paternal imprinting (silencing) of the gene  results in mutation that affects the maternal allele then complete loss of Gsα expression in the kidney, while a mutation in normally expressed paternal allele has no effect on Gsα levels  mutation of both alleles  50%  in Gsα in tissues other than the kidneys &pituitary since GNAS1 is expressed from both copies of the gene 2 Types of Pseudohypoparathyroidism (depends on parent of origin of mutant allele) a) PSEUDOHYPOPARATHYROIDISM TYPE 1A - assoc w/ multihormone resistance & Albright hereditary osteodystrophy (AHO) - skeletal & developmental defects - pts often have short stature, obesity, short metacarpal & metatarsal bones, variable mental deficits - multihormone resistance involves: PTH, TSH, LH/FSH (all activate Gsα-mediated pathways in target tissues - PTH resistance – most obvious clinical manifestation; presenting as hypocalcemia, hypophosphatemia, elevated circulating PTH -TSH resistance – generally mild - LH/FSH resistance – hypergonadotropic hypogonadism in females; mutation is inherited on maternal allele, severly impeding actions of PTH on the kidney in maintaining calcium homeostasis b) PSEUDOPSEUDOHYPOPARATHYROIDISM - mutation inherited from paternal allele - characterized by AHO w/o accompanying multihormonal resistance - serum calcium, phosphate, PTH: ALL NORMAL PANCREAS

▪Normal Blood glucose range: 70-120 mg/dl ▪3 criteria for diagnosis of diabetes: o o o

Random glucose > 200 mg/dl + classical signs and symptoms Fasting glucose > 126 mg/dl on more than one occasion Abnormal OGTT, in w/c glucose is >200mg/dl 2 hrs after a standard carbo load ** any one of these can establish diagnosis of diabetes

▪Indivs w/ fasting glucose < 110mg/dl, or less than 140 mg/dl following an OGTT  euglycemic

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▪Fasting glucose >110, but, <126, or OGTT > 140, but < 200 impaired glucose tolerance (IGT) Classification ▪The vast majority of cases of diabetes fall into one of two broad classes: o Type 1: absolute def of insulin caused by pancreatic B-cell destruction (10%) o Type 2: combi of peripheral resistance to insulin axn and inadequate secretory response by pancreatic B-cells ▪The long term complications in kidneys, eyes, nerves, and blood vessels are the same as are the principal causes of morbidity and death Normal Insulin Physiology

▪Normal glucose homeostasis is tightly regulated by three processes: o Glucose production in liver o Glucose uptake and utilization by peripheral tissues o Actions of insulin and counter-regulatory hormones, including glucagons, on glucose ▪Insulin and glucagons: opposing effects

▪Fasting states, low insulin, high glucagons levels  hepatic gluconeogenesis and glycogenolysis while decreasing glycogen synth  prevent hypoglycemia ▪Fasting plasma glucose levels determined primarily by hepatic glucose output ▪Meal  insulin levels rise, glucagons levels fall Regulation of Insulin Release

▪B-cell of the pancreatic islets ▪Preproinsulin o

o o o

Synth in RER and delivered to golgi apparatus Proteolytic steps  mature insulin and Cpeptide The most important stimulus that triggers insulin synthesis and release is glucose itself A rise in blood glucose levels results in glucose uptake into pancreatic Bcells, facilitated by an insulin-independent glucose-transporting protein, GLUT-2

Insulin Action and Insulin Signaling Pathways

▪Insulin: most potent anabolic hormone ▪Its principal metabolic function is to increase the rate of glucose transport into certain cells in the body (striated cells and adipocytes) ▪Glucose uptake in other peripheral tissues is insulinindependent ▪The anabolic effects of insulin are attributable to increased synthesis and reduced degradation of glycogen, lipids and proteins ▪Insulin also has mitogenic functions

Pathology – Endocrine Pathology by Dr. Yabut

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▪Binding of insulin  cascade of protein

▪Autoantibodies againt islet cells and insulin are also

phosphorylation and dephosphorylation ▪MAPK pathway: responsible for mitogenic effects

detected in blood of 70% to 80% of patients o The autoantibodies are reactive with a variety of B cell antigens, including glutamic acid decarboxylase (GAD)

▪PI-3K: metabolic effects

Genetic Susceptibility

▪Putative susceptibility genes have been mapped to

Hormone production in pancreatic islet cells. Immunoperoxidase staining shows a dark reaction product for insulin in cells (A), glucagon in cells (B), and somatostatin in c  ells (C)

at least 20 loci ▪The most important locus is the class II MHC (HLA) MHC Locus ▪Chromosome 6p21 (HLA-D) ▪DQB1*0302 allele is considered the primary determinant of susceptibility for the HLA-DR4 haplotype ▪HLA-DQB1*0602 allele is considered “protective” against diabetes Non-MHC Genes

▪The first disease-associated non-MHC gene to be identified was insulin ▪Mechanism of association is unknown

▪Another gene has been shown to be associated with the disease, encoding the T-cell inhibitory receptor CTLA-4 ▪Pxs with type 1 diabetes show increased frequency of a splice variant that may abrogate the normal ability of this receptor to keep self-reactive T lymphocytes under control Environmental Factors

Metabolic actions of insulin in striated muscle, adipose tissue, and liver. Pathogenesis of Type 1 DM

▪Most commonly develops in childhood, becomes manifest at puberty, and progress with age ▪Can develop at any age

▪An autoimmune dse in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined B cell antigens Mechanisms of B cell destruction:

▪Infections ▪Epidemiologic studies suggest a role of viruses ▪Association of coxsackieviruses of group B and pancreatic diseases, including diabetes ▪Mumps, measles, CMV, rubella, and infectious mononucleosis are also implicated to trigger autoimmunity ▪Infections induce tissue damage and inflammation, leading to release of B-cell antigens and the recruitment and activation of lymphocytes and other inflammatory leukocytes in tissues ▪Virus produce proteins that mimic self-antigens and the immune response to the viral protein cross-reacts w/ the self tissue

▪The classic manifestation of DM (hyperglycemia and ketosis) occur late in its course ▪T lymphocytes react against B cell antigens and cause cell damage o CD4+ T cells of the TH1 subset w/c cause tissue injury o CD8+ cytotoxic T cells w/c directly kill B cells and secrete cytokines that activate macrophages o Insulitis: necrosis and lymphocytic infiltration of the islets ▪Locally produced cytokines damage B cells o IFN-γ, TNF, and IL-1  induce B cell apoptosis

Insulin action on a target cell. Insulin binds to the

subunit of insulin receptor, leading to activation of the kinase activity in the -subunit, and sets in motion a

Pathology – Endocrine Pathology by Dr. Yabut hosphorylation (i.e., activation) cascade of multiple downstream target proteins. Pathogenesis of Type 2 DM

▪Sedentary lifestyle, dietary habits play a role ▪Genetic factors are even more important than in type 1 DM ▪The 2 metabolic defects that characterize type 2 diabetes are: o Decreased ability of peripheral tissues to respond to insulin o B-cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia ▪In most cases, insulin resistance is the primary event Insulin Resistance

▪Resistance to the effects of insulin or glucose uptake, metabolism and storage ▪Characteristic of most pxs w/ typ2 diabetes and almost universal finding in diabetic indivs who are obese ▪Insulin resistance is often detected 10-20 yrs before the onset of diabetes in predisposed indivs ▪In prospective studies, insulin resistance is the best predictor for subsequent progression to diabetes ▪Functional studies in indivs w/ insulin resistance have demonstrated numerous quantitative and qualitative abnormalities of the insulin signaling pathway, including down-regulation of the insulin receptor; decreased insulin receptor phosphorylation and tyrosine kinase activity; reduced levels of active intermediates in the insulin signaling pathway; and impairment f translocation, docking, and fusion of GLUT-4-containing vesicles w/ the plasma membrane o Genetic defects of the insulin receptor and insulin signaling pathway o Obesity and insulin resistance – risk for diabetes increases as the BMI increases  Role of free fatty acids: inverse correlation between fasting plasma FFAs and insulin sensitivity  Role of adipokines in insulin resistance: leptin (acts on CNS for satiety; insulinsensitizing actions) adiponectin, resistin  Role of peroxisome proliferator-activated receptor gamma (PPAR) and thiazolidinediones (TZD): TZD acts on PPAR leading to reduction of insulin resistance B-cell Dysfunction

▪Reflects the inability of these cells to adapt themselves to the long-term demands of peripheral insulin resistance and increased insulin secretion ▪In states of insulin resistance, insulin secretion is initially higher for each level of glucose than in controls

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▪This hyperinsulinemic state is a compensation for peripheral resistance and can often maintain normal plasma glucose for years ▪Bcell dysfunction in type 2 diabetes manifests as both qualitative and quantitative defects: o Qualitative: initially subtle, seen as a loss of normal, pulsatile, oscillating pattern of insulin secretion and attenuation of the rapid first phase of insulin secretion and attenuation of the rapid first phase of insulin secretion triggered by an elevation of in plasma glucose o Quantitative: reflected by a decrease in Bcell mass, islet degeneration, and deposition of islet amyloid Monogenic Forms of Diabetes (table 24-6) ▪Maturity-Onset Diabetes of the Young (MODY) o A primary defect in B-cell dysfunction that occurs w/o B-cell loss, affecting either B-cell mass and/or insulin production o Autosomal-dominant inheritance as a monogenic defect, w/ high penetrance o Early onset, usually before age 25, as opposed to after age 0 for most pxs w/ type 2 diabetes o Absence of obesity o Lack of islet cell autoantibodies and insulin resistance syndrome o Glucokinase: implicated in MODY2 o MODY1, 3 and 5 are associated with severe B-cell insulin secretory defects w/ the full range of diabetic complications o MODY2 feature mild chronic hyperglycemia that typically does not worsen over time o Up to 50% of carriers of glucokinase mutations develop gestational DM, defined as any degree of glucose intolerance with onset or first recognition during pregnancy o Mutations or polymorphisms in the 6 known MODY genes do not appear to contribute to the dev’t of late-onset (classic) type 2 diabetes in the vast majority of pxs ▪Mitochondrial Diabetes o Inherited maternally o Encodes several genes in the oxidative phosphorylation pathway, ribosomal RNAs and 22 transfer RNAs o Caused by a primary defect in B-cell function ▪Diabetes Associated with Insulin Gene or Insulin Receptor Mutations o Rare cause of diabetes Pathogenesis of the Complications of Diabetes ▪Morbidity associated w/ long-standing diabetes of either type results from a number of serious complications (macrovascular and microvascular diseases) ▪Macrovascular dse causes accelerated atherosclerosis among diabetics  increased risk of MI, stroke, and lower extremity gangrene

Pathology – Endocrine Pathology by Dr. Yabut

▪Microvascular dse: effects are most profound in the retina, kidneys, and peripheral nerves  diabetic retinopathy, nephropathy and neuropathy ▪Diabetes is the leading cause of blindness and endstage renal dse in the western hemisphere ▪Most of the available experimental and clinical evidence suggests that the complications of diabetes are a consequence of the metabolic derangements, mainly hyperglycemia ▪3 distinct metabolic pathways: o Formation of Advanced Glycation End Products (AGEs) see table 24-7 o Activation of protein kinase C o Intracellular hyperglycemia w/ Disturbances in Polyol pathways Morphology of Diabetes and Its Late Complications

▪In most pxs, morphologic changes are likely to be found in arteries (macrovascular dse), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues Pancreas

▪Lesions are inconstant and rarely of diagnostic value ▪Distinctive changes more common in type 1 diabetes ▪Reduction in number and size of islets (esp in type 1) ▪Leukocytic infiltration of the islets (insulitis): principally compsed of T lymphocytes; may be seen in type 1 diabetes; eosinophilic infiltrates may also be found esp in infants ▪B-cell degranulation: reflects depletion of stored insulin in already damaged B cells; more common in type 1 ▪In type 2 diabetes, there may be a subtle reduction in islet cell mass ▪Amyloid replacement of islets in type 2 diabetes appears as deposition of pink, amorphous material beginning in and around capillaries and between cells ▪An increase in the number and size of islets is especially characteristic of nondiabetic newborns of diabetic mothers Diabetic Macrovascular Disease

▪The hallmark of diabetic macrovascular disease is accelerated atherosclerosis involving the aorta and large- and medium- sized arteries ▪MI caused by atherosclerosis of the coronary arteries is the most common cause of death in diabetics ▪Gangrene of the lower extremities as a result of advanced vascular disease , is about 100 times more common in diabetics than in the general population Hyaline Arteriosclerosis ▪Vascular lesion associated with HPN ▪More prevalent and more severe in diabetes and may be seen in elderly nondiabetics w/o HPN Diabetic Microangiopathy

▪One of the most consistent morphologic features of diabetes is diffuse thickening of the basement membranes

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▪Thickening is most evident in capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla ▪Diabetic capillaries are more leaky than normal to plasma proteins ▪The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy Diabetic Nephropathy

▪Kidneys are prime targets of diabetes ▪Renal failure is only second to MI as a cause of death from this dse ▪3 lesions:

• 

Glomerular lesions Renal vascular lesions, principally arteriosclerosis  Pyelonephritis, including necrotizing papillitis ▪The most important glomerular lesions are capillary basement membrane thickening, diffuse mesangial sclerosis, and nodular glomerusclerosis (PAS positive nodules  Kimmelstiel-Wilson lesion) ▪Renal atherosclerosis and arteriosclerosis constitute part of the macrovascular dse in diabetics ▪Hyaline arteriosclerosis affects not only the afferent but also the efferent arteriole ▪Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules ▪Necrotizing papillitis or papillary necrosis (special pattern of acute pyelonephritis), is much more prevalent in diabetics than in nondiabetics Diabetic Ocular Complications ▪Retinopathy, cataract formation, or glaucoma Diabetic Neuropathy

▪Central and peripheral nervous system involvement