DISEASES OF THE THYROID and PARATHYROIDDr. RamosSurgical PathologyTHYROID

develops as a tubular evagination from foramen caecum at the root of the tongue

grows downward anterior to trachea and thyroid cartilage

Abnormal descent leads to aberrant lingual or substernal thyroid

weighs 20-25 gms T3 and T4 synthesized by thyroid

and released into blood bound to TBG, albumin and prealbumin

T3 and T4 – modulate cell growth and functional activity

Undergoes hyperplasia during stress

“Goitrogens” – inhibits thyroid gland function à suppress T3T4 synthesis à TSH increases à gland enlarges

Examples:a. Anti thyroid agentsb. Iodide

Thyrotoxicosis (Hyperthyroidism) hypermetabolic state, elevated T3

and T4

more common in females, hyperfunctioning gland

S/Sx: nervousness, palpitations, rapid pulse, fatigability, weakness, weight loss, good appetite, diarrhea, heat intolerance, warm skin, excess perspiration, emotional lability, menstrual changes, fine tremors, eye changes and thyroid enlargement

Morphology: eye changes - wide-eyed

stare, proptosis skin changes – peripheral

vasodilatation cardiac changes –

arrhythmias, mild lymphocytic/eosinophilic infiltrates, mild fibrosis, fatty changes in myofiber

Others: fatty infiltration in skeletal muscle, liver osteoporosis, lymphadenopathies

Most common cause: Grave’s disease – diffuse

hyperplasia Toxic Multinodular goiter Toxic adenoma

Hypothyroidism

Cretinism During development and infancy. Mental and physical growth

retardation, dry rough skin, wide set eyes, periorbital puffiness, flat broad nose, large protuberant tongue.

Endemic or sporadic cretin

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Myxedema Slow physical and mental activity,

fatigue, lethargy, cold intolerance, general listlessness and apathy,

Periorbital edema, thick dry coarse skin, tongue enlarges, peripheral edema, constipation, flabby heart and enlarged with dilated chambers with myofiber

CAUSES OF DISTURBED THYROID FUNCTION

A. THYROIDITIS 1. Hashimoto’s Thyroiditis

(Struma lymphomatosa)2. Subacute granulomatous

Thyroiditis (De Quevains)3. Subacute lymphocytic

(Painless) Thyroiditis4. Infectious Thyroiditis5. Riedel’s Fibrous

Thyroiditis (Riedel’s Struma)

Hashimoto’s Thyroiditis (Struma lymphomatosa)

most common cause of goitrous hypothyroidism in region sufficient with iodine

major cause of non-endemic goiter in children

an organ-specific autoimmune disease

o F:M (5:1), middle age ETIOLOGY:

o defect in function of thyroid-specific suppressor T cells, autosomal dominant

o associations with HLA-DR5 and DR3

o autoantibodies against thyroid peroxidases, thyroglobulin colloid Ag, TSH receptor, etc.

o patients may suffer from other autoimmune disease like sle, sjogren syndrome, ra, pa, grave’s

MORPHOLOGYo with atrophic and goitrous

varianto enlarged nodular gland,

rubberyo replacement of parenchyma

by lymphocytes, plasma cells, immunoblasts, macrophages, with germinal centers

o hurtle cell follicles (oncocytes)o atrophic variant – small gland

with fibrosis

SIGNS AND SYMPTOMSo thyroid enlargement,

hypothyroido increase TSH and decrease

T3T4 levelso demonstrate autoantibodies,

increase risk to lymphoma

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SUBACUTE GRANULOMATOUS THYROIDITIS (DE QUEVAINS)

self-limited granulomatous thyroiditis

second to fifth decade, F:M (3:1) HLA-B35 association probable viral

etiology MORPHOLOGY

o enlarged gland, aggregation of cells around damaged follicles admixed with multinucleated giant cells enclosing naked pools of colloid – granulomatous

o later CI infiltrates and fibrosis

SIGNS AND SYMPTOMSo acute febrile reactiono painful enlargement of

thyroido hyperthyroidismo self-limited in 6-8 weeks

SUBACUTE LYMPHOCYTIC THYROIDITIS (Painless Thyroiditis)

in female, post partum period 15% of hyperthyroidism enlargement of gland, foci of

lymphocytic infiltrates with occasional interstitial fibrosis

self-limited, T3&T4 levels increased

INFECTIOUS THYROIDITIS

from microbial seeding Staphyloccocus, Streptococcus,

Salmonella, TB and fungi

RIEDEL’S FIBROUS THYROIDITIS (Riedel’s Struma)

glandular atrophy, hypothyroidism, fibrosis and adhesions to surrounding structures

mistaken for malignancy

CAUSES OF DISTURBED THYROID FUNCTION

B. GRAVE’S DISEASE TRIAD:

o hyperthyroidism – diffuse hyperplasia

o ophthalmopathy – lid lag, stare, proptosis, upper lid retraction, periorbital edema

o dermopathy – localized edema at dorsa of legs and feet

INCIDENCE:o 1-2% of female, HLA-

DR3 and B8o between Grave’s and

other autoimmune diseases

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ETIOLOGY:o autoantibodies to TSH

receptor leading to hyperfunction of gland:

o Thyroid stimulating Abo Thyrotropin-binding inhibitor

Ig – inhibits TSH bindingo Ophthalmopathy – due to

lymphocytic infiltrates in EOM and retro-orbital fibrofatty tissue, glycosaminoglycans in orbital fat

o T cell-mediated action with local release of cytokines and growth factors

MORPHOLOGY:o enlarged, meaty parenchymao tall columnar epithelium,

increase number of cells (pseudopapilla buds)

o eaten-up colloido increase lymphoid tissueo morphology may be altered

by medications

SIGNS AND SYMPTOMS:o young femaleo thyrotoxicosiso ophthalmopathyo dermopathyo thyroid enlargemento increase RAIU, decrease TSH,

increase T3 & T4

CAUSES OF DISTURBED THYROID FUNCTION

C. DIFFUSE NON-TOXIC GOITER (COLLOID GOITER)

diffuse thyroid enlargement without hypo- or hyperfunction endemic goiter

deficient intake of iodine decrease T3 & T4, increase

TSH follicle hyperplasia à

euthyroid state GOITROGENS

o Calciumo Fluorideso Cabbageo Cassavao Cauliflowero Turnipso Brussel sproutso Brassica and Crucifera

plants Non-endemic/Sporadic

Goitero F:M (8:1), puberty or

young adulto either physiologic

superimposed on or hereditary defect in thyroxine synthesis

Signs and Symptomso enlarged glando euthyroid state

MORPHOLOGY:a. Hyperplastic Stage

enlarged, hyperemic follicles lined by columnar epithelium with scanty colloid

b. Colloid Stage colloid

accumulation, markedly enlarged gland (up to 500 gms or more)

distended follicles lined by flattened epithelium filled with colloid

irregular distribution of small and distended follicles, hyperplastic foci may persist

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CAUSES OF DISTURBED THYROID FUNCTION

D. MULTINODULAR GOITER (MCAG) from simple goiters with sporadic and endemic

forms toxic or non-toxic extreme enlargement F>M MORPHOLOGY:

o nodular, enlarged gland up to 2 kg, asymmetric

o nodularity created by islands of colloid-filled or hyperplastic follicles

o random irregular scarring

o focal hemorrhage and hemosiderin deposition

o focal calcificationso miocrocysts formation

SIGNS AND SYMTPOMS:o enlarged thyroid causing

cosmetic and functional impairment

o dysphagia, choking sensation, inspiratory stridor, SVC syndrome

o signs of thyrotoxicosis - RAIU & T3&T4

o cardiac manifestations

CAUSES OF DISTURBED THYROID FUNCTION

E. TUMORS: “Thyroid Nodules”GENERALIZATIONS:

1. A solitary nodule is more likely to be neoplastic than multiple nodules.

2. Functioning “hot” nodules are more likely to be benign than malignant.

3. The younger the patient (<40), the greater the likelihood of neoplasia

4. A nodule in a male is more ominous then one in a female

I. ADENOMAS

MORPHOLOGY: discrete, completely

encapsulated masses with parenchyma different from that outside the capsule, compress surrounding non-neoplastic thyroid tissue

approximately 3-10 cms soft, fleshy, may be

hemorrhagic composed of well or poorly

developed follicles; fetal, colloid or trabecular type, spindle cell (atypical), Hurthle cell adenomas (oncocytic type)

SIGNS AND SYMPTOMS:

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o must be differentiated from malignancy

o may be “cold” or “hot”o mass may suddenly enlarge

due to intralesional hemorrhage

II. MALIGNANT TUMORS:PAPILLARY Ca 75 – 85% Well-

differentiated tumors

FOLLICULAR Ca 10 – 20%MEDULLARY Ca 5%ANAPLASTIC Ca rare

PATHOGENESIS:o Irradiation to head and neck

areao Japanese survivors to atomic

bombs (7% developed thyroid

CA)o Hashimoto’s Thyroiditiso Non-toxic nodular goitero Oncogene PTC present in 20-

30% of tumors

1. PAPILLARY CARCINOMA most common 3rd to 5th decade F:M (2-3:1) MORPHOLOGY: from small to large lesions,

often multifocal gray white, firm, calcified

areas and cystic change Composed of papillae and or

follicles lined by single or several layers of columnar epithelium, papillae with fibrovascular core

“orphan-Annie” nuclei

Nuclear grooves, eosinophilic intranuclear inclusions, psammoma bodies

Encapsulated variant – 10% of tumors

Follicular variant – mostly follicular structures devoid of papilla but nuclear detail that of Papillary

SIGNS AND SYMPTOMS: Young female, mild to

moderate thyrotoxicosis 50% neck node metastasis at

time of diagnosis à 90% survival at 20 yrs.

Favorable prognostic factors include:

Female sex Less than 20 y/o Confinement to thyroid gland Well-differentiated cytologic

morphology

2. FOLLICULAR CARCINOMA 10-20% of thyroid CA 5th-6th decade F:M (3:1) SIGNS AND SYMPTOMS: Slow growing, painless

masses6

30% 5-year survival for large lesions

MORPHOLOGY: encapsulated, difficult to

distinguish from adenoma composed of uniform

microfollicular architecture of orderly cuboidal lining cells

capsular and/or vascular invasion

little propensity for lymphatic invasion

vascular invasion is common – distant metastasis

3. MEDULLARY THYROID CARCINOMA

Neuroendocrine neoplasm of parafollicular C cell origin

5th-6th decade of life, in 3rd decade if associated with MEN

MYC: 1. secrete calcitonin2. Amyloid stroma3. 20-25% occur with MEN

Syndrome IIa and II MORPHOLOGY: discrete tumors in one lobe or

numerous nodules throughout gray tan parenchyma,

infiltrative, calcification

polygonal and spindle shaped cells in organoid nests and trabeculae, separated by fibrovascular stroma with amyloid

SIGNS AND SYMPTOMS: Mass with associated pressure

symptoms or asymptomatic Paraneoplastic syndrome

(diarrhea) Prognosis: familial form – 90%

10-year survival MEN form – 30-50% 10-year

survival

4. ANAPLASTIC CARCIOMA 5% of carcinomas Rapid growth, large tumors Aggressive, metastasize widely Variants:

1. Spindle cell2. Giant cell3. Small cell

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F. MISCELLANEOUS LESIONS THYROGLOSSAL DUCT CYST

2-3 cm midline cyst from remnants of foramen caecum may occur at any age cyst with numerous secretion,

lined by squamous or columnar epithelium with trapped thyroid follicles in adjacent wall

DISEASES OF THE PARATHYROID

PARATHYROID GLANDS 4 glands derived from pharyngeal

pouches

36-40 mg Chief cells

- predominant cell- secrete PTH

PTH FUNCTIONS: Mobilizes calcium from bone. Increases renal production of

1,25(OH)2D3, active in intestinal Ca absorption.

Increases renal tubular reabsorption of Ca thereby conserving it.

Lowers serum phosphate level by enhancing phosphaturia.

I. PRIMARY HYPERPARATHYROIDISM Result to hypercalcemia Causes:

1. Adenoma – 75-80%2. Hyperplasia – 10-15%3. Carcinoma - <5%

Incidence:1. F:M (3:1), 6th decade of

life2. 25 cases/100,000

Major effects of hyperparathyroidism:o Increase bone resorption

and calcium mobilization from skeleton.

o Increase renal tubular reabsorption and retention of Ca

o Increase renal synthesis of 1,25(OH) 2D3 enhancing GIT calcium absorption

SIGNS AND SYMPTOMS:

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o Vague symptomso Weakness and easy

fatigabilityo Affective dysfunctionso Urinary complaintso Hypercalciuria

1. Adenoma Solitary, 0.5 to 5.0

gms, encapsulated, no intervening stromal fat

Usually inferior glands are affected

Composed mostly of normal-looking, enlarged chief cells in sheets, trabeculae, follicles

2. Primary Hyperplasia Sporadic or in MEN I and

IIa All 4 glands are enlarged,

asymmetric Diffuse or nodular

hyperplasia composed predominantly of chief cells, clear cells, oxyphil cells in sheets, nests, trabeculae and follicles

Interspersed fat within hyperplastic area

3. CARCINOMA Very similar to adenoma but

with features of local invasion and metastasis

SIGNS AND SYMPTOMS:o Renal – recurrent stones,

nephrocalcinosiso Skeletal – loss of bone,

osteoporosis, OFC o GIT – peptic ulcer,

pancreatitiso CNS – HA, depression,

memory loss, seizureso Muscular – generalized

weaknesso Others: skin & eye

changes, hyperCa, hypoPO4, elevated PTH

II. Secondary Hyperparathyroidism

In patients with renal failure

phosphate retention and hypocalcemia

secondary hyperparathyroidism MORPHOLOGY:

Same as primary HP

III. Hypoparathyroidism CAUSES:

1. Surgically induced9

2. Congenital absence of all glands

3. Autoimmune disease4. Familial and metabolic

syndromes SIGNS AND SYMPTOMS:

1. Increases neuromuscular excitability

2. Mental changes3. Intracranial changes4. Calcification of lens5. Cardiac conduction

abnormalities

IV. Pseudohypoparathyroidism Abnormality in PTH-receptor

complex interaction Unresponsive to PTH Increase PTH due to decrease

serum Ca

THE ENDOCRINE PANCREAS

Review of Normal PhysiologyCELL TYPE

SYNONYM

% PRODUCTS

PRODUCT ACTION

B BETA 70 Insulin AnabolicA ALPHA 20 Glucago

nCatabolic

D DELTA 5-10

Somatostatin

Vs insulin & glycogen

PP Pancreatic Polypeptide

1 GY effects

DIABETES MELLITUSTYPE I TYPE II

SYNONYMS Insulin dependent DM (IDDM)Juvenile onsetKetosis prone DM

Non-insulin dependent DM (NIDDM)Adult onset

PATHOGENESIS Absolute lack of insulin due to reduction of B cell

Impaired insulin release and end-organ insensitivity

CAUSES: TYPE I1. Genetic susceptibility

- resides in chromosome 6 (HLA-D), CI II genes

- 50% concordance in twins2. Autoimmunity

90% with islet cell antibodies (ICA)

3. Environmental factorsa. Virusesb. Chemicalsc. Cow’s milk

CAUSES: TYPE II1. Genetic but not HLA-linked2. No evidence for autoimmunity3. No evidence of viral-induced injury4. Premature cell aging5. Amylase outside cells6. Decrese number of receptors7. Impaired post-receptor signaling

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INSULITIS IN TYPE 1 DM

ISLET WITH AMYLOID CHANGE

MECHANISMS LEADING TO DIABETIC COMPLICATIONS

1. Non-enzymatic glycosylation à advances glycosylation end products (AGE)

o HbA1c – glycosylated hemoglobin

o measure of blood glucose level

2. Increased sorbitol and fructose à OSMOSIS

MORPHOLOGY of other organs:1. Diabetic microangiopathy2. AtherosclerosisCAUSES:

a. Hyperlipidemiab. Decreases HDLc. Increased platelet

adhesivenessEFFECTS:

a. Myocardial infarctionb. Cerebral strokec. Gangrene of lower extremities

3. Diabetic Nephropathy Kidneys are the most severely

affected organ Morphology: Diffuse glomerulosclerosis Nodular glomerulosclerosis

(Kimmelsteil-Wilson) Exudative lesion Necrotizing papillitis

NEPHROSCLEROSIS

PAPILLARY NECROSIS

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Kimmelsteil-Wilson Lesion

4. Diabetic Ocular complicationsa. Retinopathy

i. Non-proliferative (background retinopathy)

ii. Proliferativeb. Cataractc. Glaucoma

5. Diabetic Neuropathy Due to damage Schwann cells

an axon Sexual impotence, bladder

and bowel dysfunction

ISLET CELL TUMORS

A. INSULINOMA B cell tumor most common of

the islet cell tumors Clinical Triad:

hypoglycemia, CNS manifestations, relief with glucose

Morphology: Majority are solitary

adenomas Yellow-brown nodules

composed of B cells

5% malignanT

B. GASTRINOMA Clinical Triad: Zollinger

Ellison Syndrome (peptic ulcer disease, gastric hypersecretion, pancreatic islet cell tumor)

MORPHOLOGY: Microscopically similar

to insulinomas; need immunocytochemistry or electron microscopy to differentiate the two

Mostly malignant (60%)

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