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Endocrine PathologyJanuary 26, 2009 lecture trans

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A. Functional Anatomy Found in a depression in the sphenoid bone (Sella turcica) Wt: 0.5g and


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B. Pathology of the Pituitary Glands1. Hyperpituitarism

hypersecretion of one or more of the trophic hormones of the anterior lobe due to:1.defect in the feedback mechanism by the hypothalamus

low level of hypothalamic stimulation makes the pituitary more active2.by functioning neoplasms

Adenoma of the adenohyphysis: 70% elaborate a single tropic hormone: prolactin, GH, ACTH. Secretion of TSH,

LH and FSH are very rare more common in men between 20-50

Signs and Symptoms

1.Gigantism (excess of GH before the closure of the epiphyseal bone)2.Acromegaly (excess of GH after closure of the epiphyseal plate)3.Hyperprolactinemia

- excess of prolactin

- amennorhea-galactorrhea syndrome- impotence and loss of libido in males

Gigantism:

Seen on the middle female

**Difference betweenacromegaly is the time offusion of the epiphyseal

plate (not fused during

childhood)

Spade like appearance of hands (left) +

the prominent jaw = acromegaly

2. Hypopituitarism Complete loss of the pituitary function

1. Sheehans syndrome

Postpartum, after a very difficult obstetric event E.g. Excessive bleeding hypovolemic shock hypoperfusion of the pituitary liquefactive necrosis

2. Simmonds syndrome

Area ofliquefactionnecrosis

3. Empty sella syndrome the arachnoid (meninges) herniated into the sella turcica compressing the pituitary gland loss of the gland due to

pressure atrophy which will eventually lead to hypopituitarism

4. Dwarfism5. Diabetes insipidus (interruption of the ADH production)

Differential Diagnosis

a. Craniopharyngioma A neoplasm characterized by the proliferation of the Rathkes pouch expanding mass of secretory cells which are

derivatives of the primitive oral cavity that are dental cell components producing enamel

Cysticlesions

with oily

fluid

-Columnar cells arranged in glandlike formation supported by

reticulin type of fibrous tissuestroma- called Ameloblastoma if found inoral cavity

M a r v i n e dUST-FMS BMD2011


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b. Rathkes cyst Remnant of pars intermedia1 may produce colloid filled cyst and may cause compression atrophy of the pituitary gland

1pars intermedia region between the anterior and the

posterior lobe Cysticlesion

Primary macroadenoma resting onsella turcica (in many instances, the

sella may be eroded by the expanding

mass of the adenoma)

Stalk

Distinctcircumscribed

mass

** take note that alladenomas are

grossly similar in

appearance, hencewe need tissue

staining

Acidophilic staining adenoma

(GH and Prolactin producing

adenoma)

Basophilic staining adenoma

(ACTH producing adenoma)

Chromophobic adenoma

(25% Prolactin producing

Immunoperoxidere er to a e 1H&E

Functioning adenomaCells in lobules without the

glandular appearance

Pituitary microadenoma:Autonomous proliferatingsecretory cells that issharply demarcated

(yellow lines) from thesurrounding normal

pituitary cells

Colloid like cyst similar to athyroid follicle in the region o

pars intermedia

f

3. Pituitary Tumors Diffuse, sinusoidal and papillary pattern

1. Pituitary Adenoma (mostly are functioning adenoma)

a. Microadenoma (10mm in diameter) Notorious for causing pressure or mass effects Press on the CN III, IV and VI, Hypothalamus, cavernous sinus and the Optic chiasm

2. Pituitary Carcinoma (very rare)


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A. Functional Anatomy Normally four in number (2 at the left lobe and 2 on the right) small glands embedded in the posterior aspect of the thyroid substance, however, anatomic variation in numbers may occur (3 to 8)

and also variation in location (thymus and mediastinum) Derived from the 3rd and 4th brachial pouches (endoderm)

yellowish-brown, flattened nodules each weighing approximately 35-45mg made up of both parenchymal cells(secretory) and stromal cells (supporting tissue with fat deposits) Histology:

1. chief cells spheroidal cells that produce much of the parathyroid hormone (PTH)2. oxyphil cells homogenous, granular, eosinophilic cytoplasm3. clear cells

B. Pathology of the Parathyroid Gland1. Hyperparathyroidism Excessive amount of PTH Classification:

a. Primary Problem is in the parathyroid gland itself (neoplasm #1 and #2)

1. Parathyroid Adenoma (80%)

2. Parathyroid Carcinoma (2-3%) rare!3. Primary parathyroid (chief cell) hyperplasia (15%) adaptive changes

Intimate association of the fatthat blends with the verycellular structure of the gland

Grossly: can be mistaken as a

small lump of fat

Rule: malignancies usuallyinvolve one (1) gland only

while in hyperplasticchanges, it involves all of

the parathyroid glands

Effects of PTH-mobilization of Ca2+

a. induces osteoclastactivity

b. renal tubularabsorption of Ca2+

c. urinary phosphatesecretion

d. GI Ca2+ absorption

4. Component of MEN syndromei. Multiple tumors or Hyperplastic lesion involving multiple endocrine organs

PTH, hypercalcemia, hypophosphatemia and hypercalciuria Effects:

a. Nephrolithiasis/ Nephrocalcinosis (stones in the kidney)b. Metastatic calcification (in the case of neoplasm of the parathyroid)c. Generalized osteitis fibrosa cystica (punctuation of the bone due to immobilization of Ca2+)d. Depression, anxiety, coma, psychosis and hypertension* (due to hypercalcemia)

Fatty stroma

Hyperplasia of

the clear cells

Hyperplasia ofthe oxyphilic

and some of the

chief cells

Differential of Adenoma to Carcinoma1. Capsular invasion2. Metastasis

Malignant neoplasm:Overwhelming metastasis or breakage ofthe capsule or invasion of the nearby

blood vessel

Normal tissue

Capsule

Adenoma



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Page 5 of 15b. Secondary

Problem do not lie in the parathyroid itself but from a condition in which it stimulates the gland Ca2+ levels stimulate the compensatory hyperplasia = PTH production

a. Chronic renal insufficiency ( Ca2+ excretion)b. Vitamin D deficiency (dietary)c. Intestinal malabsorption syndrome (anatomic defect)d. Hyperphosphatemia

c. Tertiary Complication of the secondary hyperparathyroidism Persistent hyperplastic change despite the correction of the hypocalcemic state An autonomous nodule may have formed that continue to secrete PTH

2. Hypoparathyroidism Loss of PTH function hypocalcemic states Mostly by iatrogenic causes:

a. Surgically induced (No re-implantation of the parathyroid gland after thyroidectomy)b. Congenital absence of the glandsc. Familial hypoparathyroidism (autoimmune polyendocrine syndrome type 1)d. Idiopathic hypoparathyroidism

Effects:a. Tetany characterized by neuromuscular irritability (+ Chvostek sign and Trousseau sign)

-earliest manifestationb. Mental status changec. Ocular disease (cataract)d. Intracranial manifestatione. Cardiovascular manifestation

Long standing effects

f. Dental abnormalities

3. Tumors of the Parathyroid glands Parathyroid Adenoma - common Parathyroid Carcinoma - rare

A. Functional Anatomy Starts as a primitive anlage foramen caecum Descends thyroglossal duct in the midline (up to the C4-C6 level) expand laterally into left and right lobes and some vestige of

pyramidal lobe lobes: 2 lateral, 1 isthmus & pyramidal weight: 15-20 grams blood supply: superior and inferior thyroid arteries/ veins Histology

o 20-40 dispersed rounded follicles lined by simple cuboidal (follicular) epithelium w/ central colloid (thyroglobulin)

Follicle with rich

colloid content

Single layer of

cuboidal cells

Gross Thryoid: Similar to a

shield, Thyreos (gk)

Tryrotrophs are stimulated by the hypothalamus via the TRH TSH stimulates the thyroid follicular cells to liberate T3 and T4 from

thyroglobin T3 and T4 binds to a plasma protein TBG

Parafollicular C cells produces calcitonin that lowers the plasma Ca2+ levels



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*Ask the Px to swallowand take note of themovement of the cyst

Cyst lined by stratifiedsquamous epitheliumwith remnants of the

thyroid anlage **Px adviced for surgicalremoval due to highprobability of harboring

malignancyGross: Thyroidcovered in colloid

(yellow appearance)

Prominent mound along theanterior neck region that

goes up upon swallowing

B. Pathology of the Thyroid Gland

1.

Hyperthyroidism Excess release of the thyroid hormones ( leakage in plasma = thyrotoxicosis) T3, T4 by hyperfunctioning gland

o e.g. Graves disease may be caused by Primary or secondary hyperthyroidism

Laboratory TSH a measure of pituitary function T3 with T4 are for the circulating thyroid hormones T4 commonly measured because of its less protein binding capacity TSH- binding inhibitor immunoglobulin Thyroid growth stimulating immunoglobulin (TSI)

Clinical manifestation Tachycardia, palpitations, nervousness, rapid pulse

easy fatigability, muscular weakness wt loss despite of the appetite, heat intolerance warm skin, hyperhydrosis, amotional lability, menstrual changes, tremors

eye changes (exophthalmos), goiter

Causes: Diffuse hyperplasia associated w/ Graves (approx. 85% of ALL cases) Exogenous thyroid hormones (synthetic drug intake) Functioning goiter Functioning neoplasm

Thyroiditis (early phase)

Graves Disease Most common cause of hyperthyroidism Autoimmune disorder: defect in the T lymphocytes (sensitized to antigens within the thyroid) T cells signals the B cells to produce antibodies attack the TSH receptors in the thyroid cells

Binding of the autoantibody mimics TSH and causes hyperplasia and hypertrophy Triad of manifestation:

1. thyrotoxicosis due to hyperfunctioning gland2. exopthalmos3. pretibial myxedema localized, infiltrative dermopathy

Abnormal auto-antibodies

Meaty enlargement of the thyroid gland

Exophthalmos due to the

overactivity of the SNS and alsothe accumulation of loose CT

behind the eyeballs

Irregular stellate luminal border

of the follicle due to the cell #infolding towards the center(take note of the punctuated

colloid, which is due to theincreased formation of the

thyroid hormones)

Colloid with

scalloped margin

Papillary

infoldings

Genetic predisposition incited by:1. pregnancy2. iodine excess3. lithium therapy4. infections5. steroid withdrawal



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2. Hypothyroidism Deficiency of the thyroid hormones

Common causes ofhypothyroidism:

Structural or functional derangement that interferes with the production ofadequate levels of thyroid hormones

1. Hashimotos thyroiditis Defect anywhere the hypothalamic- pituitary-thyroid axis

2. radiation injury Primary (most common) or secondary

3. surgical ablation Clinical Manifestation 4. drugs (PTU, lithium)1. Cretinism

5. Infiltrative diseases(Sarcoidosis, TB)

Hypothyroidism developing in infants and children Caused by inborn errors of metabolism and/or Iodine deficiency

6. Primary idiopathichypothyroidism

Impaired development of CNS and etc.2. Myxedema (Gulls disease)

Hypothyroidism developing in older children and adults cretinoid state in adults Mental sluggishness and generalized apathy Accumulation of mucopolysaccharide-rich edema in skin, visceral sites and others

3. Thyroiditis Inflammatory lesions Infections are very rare in the thyroid due to its high vascularity

a. Acute thyroiditis Infectious

b. Subacute thyroiditis Granulomatous (Type IV hypersensitivity) Associated with viral infection (post viral URTI) **De Quervains thyroiditis Can also occur in Parasitic, Fungal infection of the thyroid or foreign body reaction Ssx: Pain, fever and thyroid mass Usually localized, rarely are the diffused pattern of inflammation Histology: Granuloma formation! (giant cells and histiocytes) with atrophic follicles and no colloid

Giant cells

Wood-like appearance

Granuloma

FormationFocal involvement of the thyroid

(compare to the other side)

c. Fibrous tyroiditis Riedel struma or ligneous thyroiditis (woody hardness) Rare condition (elderly female) Thyroid is normal, there is a fibrosis reaction in the neck area that will

enclose the thyroid gland and eventually destroy it. confused with a

malignancy Marked atrophy of the follicles replaced by extensive collagenous fibrosis

d. Hashimotos thyroiditis (struma lymphomatosa) Most common cause of hypothyroidism Autoimmune inflammatory disorder (HLA-DR3 and HLA-DR5) destruction of the gland T cell defect stimulates B cells to produce anti-thyroglobulin, thyroid peroxidase Ab and anti TSH Anti-TSH receptor Ab blocks the action of TSH hypothyroidism Thyroid becomes heavily infiltrated by WBC that it mimics the appearance of a lymph node

(histologically similar to a lymphoid follicle) Painless fibrosis diffuse enlargement, symmetrical (not hyperplasia!) TSH in response to T4 and T3 hashitoxicosis: intial surge of T hormones due to release via destruction of the gland

Marked stuntedgrowth, obese due

to the hypothyroid

state

Normal Cretin M a r v i n e dUST-FMS BMD2011

Inactive thyroid - does not take in the

radioactive iodine


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Follicular adenomamay have the

propensity to havehemorrhagic

degeneration andcystic change similarto an adenomatousgoiter making it hard

to differentiate them

with each other

Hurtle cells-enlargedeosinophilicgranular

cytoplasm

containing cellsDiffuse

enlargement of

the gland, it canbe nodular. It has

a fleshy lymphnode like

appearance Denselymphocytic

infiltrates

Deposition of the

autoantibodies inimmunofluorescence

(Type III hypersensitivity)

Lymphocytic

infiltrates

Lack of

thyroglobulinHurtle cells

4. Tumors of the Thyroid Gland Benign

o Follicular Adenoma Malignant All follicular

neoplasms(adenoma orcarcinoma) arenonfunctioning

tumors

o Papillary Carcinoma 75-85%o Follicular Carcinoma 10-20%o Medullary Carcinoma 5%o Anaplastic Carcinoma rare

a. Follicular Adenoma Discrete solitary mass of


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Normal thyroidAdenoma

Intactcapsule

with novascular

invasion

Microfollicles devoid of colloid

Microfollicular adenoma

Follicular adenoma--Hurtle cell variant:propensity to invade and high recurrence rate

Hurtle cells:

Large granular

acidophilic cells

Intact stroma

Normal thyroidAdenoma

b. Follicular Carcinoma Slowly enlarging painless nodule (occur in elderly) Mostly cold nodules (nonfunctioning) with some warm nodules (hyperdunctioning) If the pathology is seen microscopically follicular CA w/ minimal invasion; If Gross follicular CA with wide invasion Gross: **thickly encapsulated Histology: transcapsular invasion and vascular invasion Vascular spread bone, lung, liver and brain

c. Papillary Carcinoma Most common (all ages, females>males, risk in exposure to radiation, gardners syndrome) Solitary and multicentric neoplasm (many foci) Papillary cauliflower like granular lesions Margins are infiltrative and irregular (not regular) Psoamomma bodies area of fibrosis and calcifications Cystic degeneration

both in primary and metastatic foci (same as with goiter = not all cyst are benign) Histology:

o Orphan annie (empty appearing nucleus/ ground glass appearance)o Psoammoma bodieso Multinucleated giant cells

Solitary foci

but can bemulticentric

Intrathyroid

metastasisCapsulatedvariant

Cystic

degeneration



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Papillae with afibrovascular

core

Capillary

Orphan annie nuclei

Complex

papillary fronds

Papillary Carcinoma variants

1. Encapsulated2. Tall cell3. Hurtle cell4. Diffuse sclerosing marked lymphatic invasion5. Papillary microcarcinoma (Occult sclerosing papillaty carcinoma)

**Manifestation of the Px with metastasis large cervical nodes6. Mixed papillary follicular carcinoma

Follicular neoplasm with papillary architecture

Papillary

Microcarcinomavariant

(


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d. Medullary Carcinoma (poorly differentiate CA) Neuroendocrine neoplasm derived from Parafollicular (C) cells Secretes calcitonin Sporadic or associated in MEN syndrome Gross: somewhat the same with papillary CA Histology: Amyloid deposits pathognomonic for medullary CA

Amyloid deposits

H&E

Congo red

e. Anaplastic Carcinoma Worst cancer of the thyroid (


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Morphology Exogenous glucocorticoids causes bilateral atrophy of the adrenal cortices due to the suppression of

the endogenous ACTH. (no stimulation = atrophy)

**only the fasciculata and the reticularis are the ones affected and not the glomerulosa (independentof ACTH)

Endogenous glucocorticoids causes bilateral hyperplastic states

Primary adrenocortical neoplasmso Adenoma encapsulated, expansile, yellow tumors(lipid rich cells)o Carcinoma larger than the adenoma

**take note of the bilateral enlargement of the hyperplastic states that differentiates it from theneoplastic counterpart

Clinical Feature

Early: Hypertension and weight gain

Late: Truncal obesity, moon fascies, buffalo hump

Causes selective atrophy of the fast twitch (type II) muscle fibers = muscle mass

Hyperglycemia, glucosuria and polydipsia (gluconeogenesis and glucose uptake by the cell)

Osteoporosis

Hirsutism and menstrual abnormalities

Mental disturbances

b. Hyperaldosteronism levels of aldosterone = Na retention and K excretion = hypertension (surgically correctable) and

hypokalemia

due not suppress ACTH secretion = cortex is not atrophic

1. Primary Hyperaldosteronism Decreased plasma rennin activity due to overproduction of aldosterone

2. Secondary Hypersldosteronism Increase aldosterone release due to activation of the renin-angiotensin system = levels of

plasma renin

Morphology:

Aldosterone secreting adenoma (80%) Conns syndromeo Solitary or multiple

Primary adrenocortical hyperplasia (15%) idiopathico Diffusely or irregularly hyperplastic

c. Adrenogenital syndrome Virilization

Primary gonadal disorders and several primary adrenal disorders Congenital adrenal hyperplasia

o Autosomal recessive disorderso cortisol production ACTH secretion = adrenal hyperplasiao 21 hyroxylase deficiency

mutation in the 21-hyroxylase gene on chromosome 6



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Page 13 of 15Morphology:

bilateral adrenal hyperplasia + corticotroph (ACTH producing) cells hyperplasia in anterior pituitarygland

Bilateral

atrophy

Bilateral

hyperplasia

Clinical Features:

21-hydroxylase deficiency excess androgen activityo masculinization in females, clitoral hypertrophy and pseudohermaphrodism in infantso enlargement of the genitalia in males and oligospermia

Masculinization ofthe female external

genitalia

17-hydroxylase deficiency Androgen deficiencyo absence of secondary sexual characteristics in females and pseudohermaphrodism in male

- sodium wasting

2. Hypoadrenalism or adrenal insufficiency Primary adrenal disease Secondary stimulation due to ACTH deficiency

a. Acute Adrenocortical insufficiency Due to a rapid withdrawal of steroids or failure to increase steroid doses in response to stress from chronic AI Massive adrenal hemorrhage may also destroy cortex to cause acute ardrenocortocal insufficiency May also be caused by overwhelming sepsis (Waterhouse-Friderichsen syndrome)

Endotoxin-induced vascular injury with DIC

b. Chronic Adrenocortical insufficiency (Addisons disease)- progressive destruction of the adrenal cortex- clinical sign do not appear if


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Microscopic

Composed chromaffin cells and their supporting cells compartmentalized into small nest or Zellbalen by a richvascularized network

Granular cytoplasm (highlighted by silver stains presence of catecholamines)

Zellbalen withgranular

chromaffincells

surrounded by

capillaries

Presence ofnuclear

pleomorphism

2. Neuronal neoplasms (neuroblastoma and mature ganglion cell tumors) Most common extra-cranial solid tumor of childhood May arise anywhere in the sympathetic nervous system (mostly in adrenal medulla)

Multiple Endocrine Neoplasia (MEN syndromes) A group of inherited diseases resulting into proliferative lesions of multiple endrocine organs

MEN Type 1 Autosomal dominant pattern

MEN1 tumor suppressor gene MEN Type 2

Mutations of the RET oncogene at chromosome 10q11.2 Autosomal dominant pattern Different mutation pattern = different type

Endocrine OrganMEN I

(Wermers syndrome)

MEN II or IIa

(Sipples syndromeMEN IIb or III

Pituitary Adenomas

Parathyroid HyperplasiaAdenomas

Hyperplasia

Pacreatic islets HyperplasiaAdenomas

Carcinoma

Adrenal Cortical Hyperplasia Phaeochromocytoma Phaeochromocytoma

Thyroid C-cell hyperplasia Medullary carcinoma Medullary carcinoma

Extraendocrine changes Mucocutaneous ganglioneuromas

Marfanoid habitus

Mutant gene locus 11q13 10q11.2 (RET) 10q11.2 (RET)

Reference:

Kumar et. al. Robbins Basic Pathology 8th ed. 2000. Elsevier Saunders. Pages 637-665.

Kumar et al. Robbins and Cotran Pathologic Basis of Disease. 7th ed. 2005. Elsevier Saunders. Pages 1155-1224.

Acknowledgement

I would like to thank Dr. Yolo for letting me record his lecture and also Joyce Ignacio for taking pictures of the presentation tocomplete this trans, which are not seen in the powerpoint presentation of the previous batches.

Good luck in the exams! God bless!
