Patho Endocrine

ENDOCRINE DISEASESENDOCRINE DISEASES

ROBERTO D. PADUA JR.,MD, FPSPROBERTO D. PADUA JR.,MD, FPSP

DEPARTMENT OF PATHOLOGYDEPARTMENT OF PATHOLOGY

FATIMA COLLEGE OF MEDICINEFATIMA COLLEGE OF MEDICINE

PITUITARY GLANDPITUITARY GLAND

Bean-shaped organBean-shaped organ Measures 1 cm in greatest diameterMeasures 1 cm in greatest diameter Weighs about 0.5 gramsWeighs about 0.5 grams

Anterior PituitaryAnterior Pituitary

SomatotrophsSomatotrophs– Acidophilic cells; GHAcidophilic cells; GH

Lactotrophs (mammotrophs)Lactotrophs (mammotrophs)– Acidophilic cells; prolactinAcidophilic cells; prolactin

CorticotrophsCorticotrophs– Basophilic cells; ACTH, POMC, MSH, endorphins, Basophilic cells; ACTH, POMC, MSH, endorphins,

lipotropinlipotropin ThyrotrophsThyrotrophs

– Basophilic cells; TSHBasophilic cells; TSH GonadotrophsGonadotrophs

– Basophilic cells; FSH, LHBasophilic cells; FSH, LH

Clinical Manifestations of Pituitary Clinical Manifestations of Pituitary DiseaseDisease

HyperpituitarismHyperpituitarism– Arising from excess secretion of trophic hormonesArising from excess secretion of trophic hormones– Causes: pituitary adenoma, hyperplasia and carcinomas of the anterior Causes: pituitary adenoma, hyperplasia and carcinomas of the anterior

pituitary, secretion of hormones by non-pituitary tumors, and certain pituitary, secretion of hormones by non-pituitary tumors, and certain hypothalamic disordershypothalamic disorders

HypopituitarismHypopituitarism– Ischemic injury, surgery or radiation, inflammatory reactions, Ischemic injury, surgery or radiation, inflammatory reactions,

nonfunctioning adenoma, pituitary apoplexy, Sheehan’s syndrome, Rathke nonfunctioning adenoma, pituitary apoplexy, Sheehan’s syndrome, Rathke cleft cyst, empty sella syndrome, genetic defectscleft cyst, empty sella syndrome, genetic defects

Local mass effectsLocal mass effects– Earliest changes are radiographic abnormalities of the sella turcicaEarliest changes are radiographic abnormalities of the sella turcica

Sellar expansion, bony erosion, and disruption of diaphragma sella Sellar expansion, bony erosion, and disruption of diaphragma sella – Bitemporal hemianopsia; increase ICPBitemporal hemianopsia; increase ICP– Pituitary apoplexy – acute hemorrhage into an adenoma with rapid Pituitary apoplexy – acute hemorrhage into an adenoma with rapid

enlargement of the lesionenlargement of the lesion Disease of Posterior pituitary come to clinical attention due to increase Disease of Posterior pituitary come to clinical attention due to increase

or decrease secretionor decrease secretion

Pituitary Adenomas and Pituitary Adenomas and HyperpituitarismHyperpituitarism

Most common cause of hyperpituitarism is an Most common cause of hyperpituitarism is an adenoma arising in the anterior lobeadenoma arising in the anterior lobe

Pituitary adenomas are classified on the basis of Pituitary adenomas are classified on the basis of hormone(s) produced by the neoplastic cells hormone(s) produced by the neoplastic cells detected by immunohistochemical stains detected by immunohistochemical stains performed on tissue sectionsperformed on tissue sections

Can secrete two hormones (GH and PRL);rarely Can secrete two hormones (GH and PRL);rarely plurihormonalplurihormonal

May be hormone-negative – may cause May be hormone-negative – may cause hypopituitarism hypopituitarism

Pituitary Adenomas and Pituitary Adenomas and HyperpituitarismHyperpituitarism

10% of intracranial neoplasms10% of intracranial neoplasms Incidental findings in autopsies – 25%Incidental findings in autopsies – 25% 3% of cases are assoc. with MEN type 13% of cases are assoc. with MEN type 1 Microadenomas = less than 1 cmMicroadenomas = less than 1 cm Macroadenomas = more than 1 cmMacroadenomas = more than 1 cm

Genetic abnormalities associated Genetic abnormalities associated with Pituitary adenomaswith Pituitary adenomas

Monoclonal in origin Monoclonal in origin From a single somatic cellFrom a single somatic cell

G-protein mutations G-protein mutations Role in signal transductionRole in signal transduction Best characterized molecular abnormalitiesBest characterized molecular abnormalities

Association with MEN syndromeAssociation with MEN syndrome MEN1MEN1 gene on chromosome 11q13 gene on chromosome 11q13

Mutations of the Mutations of the RASRAS oncogene and oncogene and overexpression of the overexpression of the c-MYCc-MYC oncogene oncogene

Aggressive or advanced pituitary adenomasAggressive or advanced pituitary adenomas

Pituitary adenoma - MorphologyPituitary adenoma - Morphology

Soft, well-circumscribed lesion confined to Soft, well-circumscribed lesion confined to the sella turcicathe sella turcica

Larger lesions extend into the suprasellar region, Larger lesions extend into the suprasellar region, compress the optic chiasm and adjacent structurescompress the optic chiasm and adjacent structures

30% of cases extend into the cavernous and 30% of cases extend into the cavernous and sphenoid sinusessphenoid sinuses

Not grossly encapsulated and infiltrate adjacent Not grossly encapsulated and infiltrate adjacent bone, dura, and rarely the brain and has no ability for bone, dura, and rarely the brain and has no ability for distant metastasis (invasive adenoma)distant metastasis (invasive adenoma)

Foci of hemorrhage and necrosis are common in Foci of hemorrhage and necrosis are common in larger adenomaslarger adenomas

Pituitary adenoma - MorphologyPituitary adenoma - Morphology

Composed of relatively uniform, polygonal Composed of relatively uniform, polygonal cells arrayed in sheets or cordscells arrayed in sheets or cords

Nuclei may be uniform or pleiomorphicNuclei may be uniform or pleiomorphic Modest mitotic activityModest mitotic activity Cytoplasm maybe acidophilic, basophilic, or Cytoplasm maybe acidophilic, basophilic, or

chromophobicchromophobic

ProlactinomaProlactinoma

Lactotroph adenomasLactotroph adenomas Comprising about 30% Comprising about 30% Majority are weakly acidophilic or Majority are weakly acidophilic or

chromophobic (sparsely granulated chromophobic (sparsely granulated prolactinoma); rare are strongly acidophilic prolactinoma); rare are strongly acidophilic (densely granulated prolactinoma)(densely granulated prolactinoma)

Undergo dystrophic calcificationUndergo dystrophic calcification Psammoma bodiesPsammoma bodies ““pituitary stone”pituitary stone”


Prolactinemia – increase prolactin levelProlactinemia – increase prolactin level Amenorrhea, galactorrhea, loss of libido, and infertilityAmenorrhea, galactorrhea, loss of libido, and infertility

Physiologic prolactinemiaPhysiologic prolactinemia Pregnancy, suckling in lactating women, stressPregnancy, suckling in lactating women, stress

Pathologic prolactinemiaPathologic prolactinemia Lactotroph hyperplasia – interference with normal dopamine inhibition Lactotroph hyperplasia – interference with normal dopamine inhibition

of prolactinof prolactin STALK EFFECT – any mass in the suprasellar STALK EFFECT – any mass in the suprasellar

compartment may disturb the normal inhibitory influence of compartment may disturb the normal inhibitory influence of the hypothalamus on prolactin secretion resulting in the hypothalamus on prolactin secretion resulting in hyperprolactinemiahyperprolactinemia

******Therefore, a mild elevation in serum prolactin in a patient Therefore, a mild elevation in serum prolactin in a patient with a pituitary adenoma does not necessarily indicate a with a pituitary adenoma does not necessarily indicate a prolactin-secreting tumor.prolactin-secreting tumor.


Other causes of hyperprolactinemiaOther causes of hyperprolactinemia Drugs – neuroleptic (phenothiazines, haloperidol), Drugs – neuroleptic (phenothiazines, haloperidol),

anti-hypertensive (reserpine)anti-hypertensive (reserpine) EstrogensEstrogens Renal failureRenal failure hypothyroidismhypothyroidism

Treatment : surgery or with Bromocriptine, a Treatment : surgery or with Bromocriptine, a dopamine receptor agonistdopamine receptor agonist

Growth Hormone (Somatotroph cell) Growth Hormone (Somatotroph cell) AdenomasAdenomas

22ndnd most common type of functioning most common type of functioning pituitary adenomaspituitary adenomas

Express a mutant GTPase-deficient alpha-Express a mutant GTPase-deficient alpha-subunit of the G-proteinsubunit of the G-protein

HistologyHistology– Densely granulatedDensely granulated

Cells are monomorphic and acidophilicCells are monomorphic and acidophilic

– Sparsely granulatedSparsely granulated Composed of chromophobe cells Composed of chromophobe cells


Mammosomatotroph adenomasMammosomatotroph adenomas BihormonalBihormonal Reactive for both GH and prolactinReactive for both GH and prolactin

Persistent hypersecretion of GH stimulates Persistent hypersecretion of GH stimulates the hepatic secretion of insulin-like growth the hepatic secretion of insulin-like growth factor (IGF-I or somatomedin C)factor (IGF-I or somatomedin C)

Responsible for many clinical manifestationsResponsible for many clinical manifestations


Clinical manifestationsClinical manifestations– GigantismGigantism

Appears in children before epiphyseal closureAppears in children before epiphyseal closure Genralized increase in body size with Genralized increase in body size with

disproportionately long arms and legsdisproportionately long arms and legs

– AcromegalyAcromegaly Increased levels of GHvare present after closure of Increased levels of GHvare present after closure of

the epiphysisthe epiphysis Affects the skin and soft tissues; viscera (thyroid, Affects the skin and soft tissues; viscera (thyroid,

heart, liver, and adrenals); bones of the face, hands, heart, liver, and adrenals); bones of the face, hands, and feetand feet


ACROMEGALYACROMEGALY Increased bone density (hyperostosis) in both the Increased bone density (hyperostosis) in both the

spine and hipsspine and hips Enlargement of the jaw results in protrusion Enlargement of the jaw results in protrusion

(prognathism) with broadening of the lower face(prognathism) with broadening of the lower face Enlarged hands and feet with broad sausage-like Enlarged hands and feet with broad sausage-like

fingersfingers


DiagnosisDiagnosis Elevated serum GH and IGF-I levelsElevated serum GH and IGF-I levels Failure to suppress GH production in response to an Failure to suppress GH production in response to an

oral load glucose is one of the most sensitive test for oral load glucose is one of the most sensitive test for acromegalyacromegaly

TreatmentTreatment Restore GH levels to normal and to decrease Restore GH levels to normal and to decrease

symptomssymptoms Surgery, radiation therapy, or by drug therapySurgery, radiation therapy, or by drug therapy

Corticotroph Cell AdenomasCorticotroph Cell Adenomas

Usually small microadenomasUsually small microadenomas Most often basophilic and occasionally Most often basophilic and occasionally

chromophobicchromophobic Stain positively with PAS due to POMCStain positively with PAS due to POMC Immunoreactivity for POMC and its Immunoreactivity for POMC and its

derivatives – ACTH and beta-endorphinderivatives – ACTH and beta-endorphin Leads to adrenal hypersecretion of cortisol Leads to adrenal hypersecretion of cortisol

leading to hypercortisolism (Cushing leading to hypercortisolism (Cushing syndrome)syndrome)

Corticotroph Cell AdenomasCorticotroph Cell Adenomas

Cushing diseaseCushing disease Pituitary CushingPituitary Cushing

Nelson syndromeNelson syndrome Large destructive adenomas developing in patients Large destructive adenomas developing in patients

after surgical removal of the adrenal glands for after surgical removal of the adrenal glands for treatment of Cushing syndrometreatment of Cushing syndrome

Due to loss of the inhibitory effect of adrenal Due to loss of the inhibitory effect of adrenal corticosteroids on a pre-existing corticotroph corticosteroids on a pre-existing corticotroph microadenomamicroadenoma

Hypercortisolism is absentHypercortisolism is absent

Gonadotroph (LH-producing and Gonadotroph (LH-producing and FSH-producing) AdenomasFSH-producing) Adenomas

Usually found in middle-aged men and Usually found in middle-aged men and women with neurologic symptomswomen with neurologic symptoms

Causes decreased energy and libido in Causes decreased energy and libido in men and amenorrhea in pre-menopausal men and amenorrhea in pre-menopausal womenwomen

Secondary gonadal hypofunctionSecondary gonadal hypofunction

Thyrotroph (TSH-producing) Thyrotroph (TSH-producing) AdenomasAdenomas

Rare, accounting for about 1% of all Rare, accounting for about 1% of all pituitary adenomaspituitary adenomas

Chromophobic or basophilicChromophobic or basophilic Rare cause of hyperthyroidismRare cause of hyperthyroidism

Non-Functioning Pituitary AdenomasNon-Functioning Pituitary Adenomas

Approximately 25% of all pituitary tumorsApproximately 25% of all pituitary tumors Typical presentation is mass effectsTypical presentation is mass effects ““null cell adenomas”null cell adenomas”

Inability to demonstrate markers of differentiationInability to demonstrate markers of differentiation It is now known that most null cell adenomas have It is now known that most null cell adenomas have

biochemical and ultrastructural features that allow biochemical and ultrastructural features that allow their characterization as silent tumors of their characterization as silent tumors of gonadotrophin lineagegonadotrophin lineage

Pituitary CarcinomasPituitary Carcinomas

RareRare Most are non-functionalMost are non-functional Diagnosis requires demonstration of Diagnosis requires demonstration of

metastasis – LN, bone, livermetastasis – LN, bone, liver

HypopituitarismHypopituitarism

Decreased secretion of pituitary hormones, which Decreased secretion of pituitary hormones, which result from diseases of the hypothalamus or of the result from diseases of the hypothalamus or of the pituitarypituitary

Hypofunction of the anterior pituitary occurs when Hypofunction of the anterior pituitary occurs when approximately 75% of the parenchyma is lost or approximately 75% of the parenchyma is lost or absentabsent

Hypopituitarism accompanied by evidence of Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of posterior pituitary dysfunction in the form of diabetes insipidus is almost always of diabetes insipidus is almost always of hypothalamic originhypothalamic origin


Causes:Causes: Tumors and other mass lesionsTumors and other mass lesions Pituitary surgery or radiationPituitary surgery or radiation Pituitary apoplexyPituitary apoplexy Ischemic necrosis of the pituitary and Sheehan Ischemic necrosis of the pituitary and Sheehan

syndromesyndrome Rathke cleft cystRathke cleft cyst Empty sella syndromeEmpty sella syndrome Genetic defectsGenetic defects


Hypothalamic lesions Hypothalamic lesions TumorsTumors

– CraniopharyngiomasCraniopharyngiomas– Metastatic lesions (breast and lung)Metastatic lesions (breast and lung)– Radiation treatment of nasopharyngeal tumorsRadiation treatment of nasopharyngeal tumors

Inflammatory disorders and infectionsInflammatory disorders and infections– SarcoidosisSarcoidosis– Tuberculous meningitisTuberculous meningitis

Posterior PituitaryPosterior Pituitary

ADH (Vasopressin)ADH (Vasopressin)– Supraoptic nucleusSupraoptic nucleus

OxytocinOxytocin– Paraventricular nucleusParaventricular nucleus

Posterior Pituitary SyndromesPosterior Pituitary Syndromes

Diabetes insipidusDiabetes insipidus ADH deficiencyADH deficiency Characterized by excessive urination (polyuria)Characterized by excessive urination (polyuria) Central – due to ADH deficiencyCentral – due to ADH deficiency Nephrogenic – renal tubular unresponsiveness to Nephrogenic – renal tubular unresponsiveness to

circulating ADHcirculating ADH Excretion of large volume of dilute urine with low Excretion of large volume of dilute urine with low

specific gravityspecific gravity Increased serum sodium and osmolalityIncreased serum sodium and osmolality Causes: head trauma, tumors and inflammatory Causes: head trauma, tumors and inflammatory

conditions involving the hypothalamusconditions involving the hypothalamus

Posterior Pituitary SyndromesPosterior Pituitary Syndromes

Syndrome of Inappropriate ADH (SIADH) Syndrome of Inappropriate ADH (SIADH) secretionsecretion

ADH excess causes resorption of excessive amounts ADH excess causes resorption of excessive amounts of free water, resulting in hyponatremiaof free water, resulting in hyponatremia

Clinical manifestations – hyponatremia, cerebral Clinical manifestations – hyponatremia, cerebral edema, and resultant neurologic dysfunctionedema, and resultant neurologic dysfunction

Causes: secretion of ectopic ADH by malignant Causes: secretion of ectopic ADH by malignant neoplasms (small cell Ca of the lung), local injury to neoplasms (small cell Ca of the lung), local injury to the hypothalamus or posterior pituitary or boththe hypothalamus or posterior pituitary or both

Hypothalamic Suprasellar TumorsHypothalamic Suprasellar Tumors

May induce hypofunction or hyperfunction of May induce hypofunction or hyperfunction of the anterior pituitary, diabetes insipidus, or the anterior pituitary, diabetes insipidus, or bothboth

Mostly are gliomas (chiasm) and Mostly are gliomas (chiasm) and craniopharyngiomascraniopharyngiomas


CraniopharyngiomasCraniopharyngiomas Derived from vestigial remnants of Rathke pouchDerived from vestigial remnants of Rathke pouch Account for 1-5% of intracranial tumorsAccount for 1-5% of intracranial tumors Bimodal age distributionBimodal age distribution

Childhood (5-15 years) – endocrine deficienciesChildhood (5-15 years) – endocrine deficiencies Adults (sixth decade or older) – visual disturbancesAdults (sixth decade or older) – visual disturbances

Encapsulated, solid but more commonly cystic and Encapsulated, solid but more commonly cystic and multiloculatedmultiloculated

Encroach on the optic chiasm and cranial nervesEncroach on the optic chiasm and cranial nerves


Adamantinomatous craniopharyngiomasAdamantinomatous craniopharyngiomas Presents with radiographic calcificationsPresents with radiographic calcifications Consists of nests and cords of stratifies squamous Consists of nests and cords of stratifies squamous

epitheliumepithelium Compact, lamellar keratin formation (“wet keratin”)Compact, lamellar keratin formation (“wet keratin”) Tumors extend fingerlets of epithelium into adjacent Tumors extend fingerlets of epithelium into adjacent

brain eliciting a brisk glial reactionbrain eliciting a brisk glial reaction

Papillary craniopharyngiomaPapillary craniopharyngioma Contain both solid sheets and papillae lined by well-Contain both solid sheets and papillae lined by well-

differentiated squamous epitheliumdifferentiated squamous epithelium Tumors lack keratin, cyst, and calcificationTumors lack keratin, cyst, and calcification

Thyroid GlandThyroid Gland

15-20 grams15-20 grams Consists of two bulky lateral lobes Consists of two bulky lateral lobes

connected in the midline by a thin isthmusconnected in the midline by a thin isthmus Located below and anterior to the larynxLocated below and anterior to the larynx

HyperthyroidismHyperthyroidism

ThyrotoxicosisThyrotoxicosis Hypermetabolic state caused by elevated Hypermetabolic state caused by elevated

circulating levels of free T3 and T4circulating levels of free T3 and T4 Most common causesMost common causes

Diffuse hyperplasia of the thyroid associated with Diffuse hyperplasia of the thyroid associated with Graves disease (85% of cases)Graves disease (85% of cases)

Hyperfunctional multinodular goiterHyperfunctional multinodular goiter Hyperfunctional adenoma of the thyroidHyperfunctional adenoma of the thyroid


Neuromuscular systemNeuromuscular system Tremors, hyperactivity, emotional lability, anxiety, inability to Tremors, hyperactivity, emotional lability, anxiety, inability to

concentrate, insomniaconcentrate, insomnia Thyroid myopathy – proximal muscle weakness with decrease Thyroid myopathy – proximal muscle weakness with decrease

muscle massmuscle mass Ocular changesOcular changes

Wide, staring gaze and lid lagWide, staring gaze and lid lag Thyroid ophthalmopathyThyroid ophthalmopathy

Gastrointestinal systemGastrointestinal system Hypermotility, malabsorption, and diarrheaHypermotility, malabsorption, and diarrhea

Skeletal systemSkeletal system Stimulates bone resorption (inc. porosity of cortical bone and Stimulates bone resorption (inc. porosity of cortical bone and

reduced volume of trabecular bone)reduced volume of trabecular bone) Osteoporosis and increased risk of fracturesOsteoporosis and increased risk of fractures


Thyroid stormThyroid storm Abrupt onset of hyperthyroidismAbrupt onset of hyperthyroidism Occurs most commonly in patients with Graves Occurs most commonly in patients with Graves

disease – acute elevation of catecholamine levelsdisease – acute elevation of catecholamine levels A medical emergencyA medical emergency Untreated patients die of cardiac arrhythmiasUntreated patients die of cardiac arrhythmias

Apathetic hyperthyroidismApathetic hyperthyroidism Thyrotoxicosis occuring in the elderlyThyrotoxicosis occuring in the elderly


DiagnosisDiagnosis Laboratory measurement of TSH, FT3, FT4Laboratory measurement of TSH, FT3, FT4 RAIURAIU TRH stimulation testTRH stimulation test

Used in suspected hyperthyroidism where results of Used in suspected hyperthyroidism where results of TSH are unequivocalTSH are unequivocal

Graves DiseaseGraves Disease

Most common cause of endogenous Most common cause of endogenous hyperthyroidismhyperthyroidism

Triad:Triad:– HyperthyroidismHyperthyroidism– Infiltrative ophthalmopathy with resultant Infiltrative ophthalmopathy with resultant

exophthalmosexophthalmos– Localized, infiltrative dermopathy (pretibial Localized, infiltrative dermopathy (pretibial

myxedema)myxedema)

Graves DiseaseGraves Disease

An autoimmune disorder with a variety of An autoimmune disorder with a variety of antibodiesantibodies– Thyroid-stimulating immunoglobulin (TSI)Thyroid-stimulating immunoglobulin (TSI)– Thyroid growth-stimulating immunoglobulins Thyroid growth-stimulating immunoglobulins

(TGI)(TGI)– TSH-binding inhibitor immunoglobulins (TBII)TSH-binding inhibitor immunoglobulins (TBII)

Gland is symmetrically enlarged because of Gland is symmetrically enlarged because of diffuse hypertrophy and hyperplasiadiffuse hypertrophy and hyperplasia

HypothyroidismHypothyroidism

Structural or functional derangement that Structural or functional derangement that interfere with the production of afequate interfere with the production of afequate levels of thyroid hormonelevels of thyroid hormone

Primary, secondary, or tertiaryPrimary, secondary, or tertiary

CretinismCretinism

Hypothyroidism that occurs in infancy or Hypothyroidism that occurs in infancy or early childhoodearly childhood

Impaired development of the skeletal Impaired development of the skeletal system and CNSsystem and CNS

Manifests as severe mental retardation, Manifests as severe mental retardation, short stature, coarse facial features, short stature, coarse facial features, protruding tongue and umbilical herniaprotruding tongue and umbilical hernia

MyxedemaMyxedema Hypothyroidism developing in the older child or adultHypothyroidism developing in the older child or adult Gull diseaseGull disease Characterized by slowing of physical and mental Characterized by slowing of physical and mental

activity activity Accumulation of matrix substances Accumulation of matrix substances

(glycosaminoglycans and hyaluronic acid) in the skin, (glycosaminoglycans and hyaluronic acid) in the skin, subcutaneous tissues, and visceral sites subcutaneous tissues, and visceral sites edema, edema, broadening and coarsening of facial features, broadening and coarsening of facial features, enlargement of the tongue, and deepening of the enlargement of the tongue, and deepening of the voicevoice

Measurement of serum TSH level is the most Measurement of serum TSH level is the most sensitive screening test sensitive screening test

Hashimoto ThyroiditisHashimoto Thyroiditis

Chronic lymphocytic thyroiditisChronic lymphocytic thyroiditis Struma lymphomatosaStruma lymphomatosa Most common cause of hypothyroidism in areas of Most common cause of hypothyroidism in areas of

the world where iodine levels are sufficientthe world where iodine levels are sufficient Pathogenesis:Pathogenesis:

– CD8+ cytotoxic T-cell mediated cell deathCD8+ cytotoxic T-cell mediated cell death– Cytokine mediated cell deathCytokine mediated cell death– Binding of anti-thyroid Ab’s Binding of anti-thyroid Ab’s ADCC ADCC

Anti-TSH receptor Ab’s, antithyroglobulin, antithyroid Anti-TSH receptor Ab’s, antithyroglobulin, antithyroid peroxidase Ab’speroxidase Ab’s

Hashimoto ThyroiditisHashimoto Thyroiditis

MorphologyMorphology– Diffusely enlarge thyroidDiffusely enlarge thyroid– Microscopic examination show extensive Microscopic examination show extensive

infiltration of the parenhyma by a mononuclear infiltration of the parenhyma by a mononuclear inflammatory infiltrate containing small inflammatory infiltrate containing small lymphocytes, plasma cells, and well developed lymphocytes, plasma cells, and well developed germinal centers, Hurtle cell metaplasiagerminal centers, Hurtle cell metaplasia

– Fibrous variant – “keloid-like”Fibrous variant – “keloid-like”

Subacute (Granulomatous) Subacute (Granulomatous) ThyroiditisThyroiditis

De Quervain thyroiditisDe Quervain thyroiditis Caused by viral infection or postviral Caused by viral infection or postviral

inflammatory processinflammatory process Multinucleated giant cells are seenMultinucleated giant cells are seen

Subacute Lymphocytic (painless) Subacute Lymphocytic (painless) ThyroiditisThyroiditis

Painless thyroiditis or silent thyroiditisPainless thyroiditis or silent thyroiditis Uncommon cause of hyperthyroidismUncommon cause of hyperthyroidism More common in women, especially during More common in women, especially during

the post-partum period (postpartum thyroiditis)the post-partum period (postpartum thyroiditis) Lymphocytic infiltration with hyperplastic Lymphocytic infiltration with hyperplastic

germinal centers within the thyroid germinal centers within the thyroid parenchyma and patch disruption and parenchyma and patch disruption and collapse of thyroid follicles collapse of thyroid follicles

Riedel ThyroiditisRiedel Thyroiditis

Rare disorder of unknown etiologyRare disorder of unknown etiology Extensive fibrosis involving the thyroid and Extensive fibrosis involving the thyroid and

contiguous neck structurescontiguous neck structures Hard and fixed thyroid massHard and fixed thyroid mass

Diffuse and Multinodular GoitersDiffuse and Multinodular Goiters

Reflect impaired synthesis of thyroid hormonesReflect impaired synthesis of thyroid hormones Diffuse nontoxic (simple) goiterDiffuse nontoxic (simple) goiter

– Diffusely involves the entire gland without producing Diffusely involves the entire gland without producing nodularitynodularity

– Enlarged follicles are filled with colloid = colloid goiterEnlarged follicles are filled with colloid = colloid goiter

Multinodular goiterMultinodular goiter– Irregular enlargement of the glandIrregular enlargement of the gland– Produce the most extreme enlargement and are more Produce the most extreme enlargement and are more

mistaken for neoplastic involvement than any other form mistaken for neoplastic involvement than any other form of thyroid diseaseof thyroid disease

Neoplasms of the ThyroidNeoplasms of the Thyroid

Clue to the nature of a thyroid noduleClue to the nature of a thyroid nodule Solitary nodulesSolitary nodules, in general are more likely to be , in general are more likely to be

neoplastic than are multiple nodulesneoplastic than are multiple nodules Nodules in younger patientsNodules in younger patients are more likely to be are more likely to be

neoplastic than are those in older patientsneoplastic than are those in older patients A history of radiation treatmentA history of radiation treatment to the head and neck to the head and neck

region is associated with an increased incidence of region is associated with an increased incidence of thyroid malignancythyroid malignancy

Nodules that take up radioactive iodineNodules that take up radioactive iodine in imaging in imaging studies (hot nodules) are more likely to be benign studies (hot nodules) are more likely to be benign than malignantthan malignant

AdenomasAdenomas

Discrete, solitary massesDiscrete, solitary masses Derived from follicular epitheliumDerived from follicular epithelium

Follicular adenomasFollicular adenomas

Classification based on the degree of follicle Classification based on the degree of follicle formation and the colloid content of the folliclesformation and the colloid content of the follicles

Majority are nonfunctionalMajority are nonfunctional ““Toxic adenomas”Toxic adenomas”

Hormone production is independent of TSH stimulationHormone production is independent of TSH stimulation Thyroid autonomy Thyroid autonomy

AdenomasAdenomas

MorphologyMorphology Solitary, spherical, encapsulated lesion that is well Solitary, spherical, encapsulated lesion that is well

demarcated from the surrounding thyroid demarcated from the surrounding thyroid parenchymaparenchyma

Lesion bulges from the cut surface and compresses Lesion bulges from the cut surface and compresses the adjacent thyroidthe adjacent thyroid

Microscopically show cells often form uniform-Microscopically show cells often form uniform-appearing follicles that contain colloidappearing follicles that contain colloid

AdenomasAdenomas

Hurthle cell adenomaHurthle cell adenoma Neoplastic cells acquire brightly eosinophilic granular cytoplasm Neoplastic cells acquire brightly eosinophilic granular cytoplasm

(oxyphil or hurthle cell change)(oxyphil or hurthle cell change) Clinical presentation and behavior is similar to conventional Clinical presentation and behavior is similar to conventional

adenomasadenomas

******** Careful evaluation of the integrity of the capsule is therefore Careful evaluation of the integrity of the capsule is therefore critical in distinguishing follicular adenomas from follicular critical in distinguishing follicular adenomas from follicular carcinomascarcinomas

*** Owing to the need for evaluating capsular integrity, the *** Owing to the need for evaluating capsular integrity, the definitive diagnosis of adenomas can be made only after definitive diagnosis of adenomas can be made only after careful histologic examination of the resected specimencareful histologic examination of the resected specimen

Thyroid NeoplasmsThyroid Neoplasms

Papillary carcinoma – 75-85% of casesPapillary carcinoma – 75-85% of cases Follicular carcinoma – 10-20% of casesFollicular carcinoma – 10-20% of cases Medullary carcinoma – 5% of casesMedullary carcinoma – 5% of cases Anaplastic carcinoma - <5% of casesAnaplastic carcinoma - <5% of cases

Robbins and Cotran, 7Robbins and Cotran, 7thth Edition Edition

Papillary CarcinomaPapillary Carcinoma

Associated with previous exposure to ionizing Associated with previous exposure to ionizing radiationradiation

Contain branching papillae with fibrovascular Contain branching papillae with fibrovascular stalkstalk

Nuclei imparts an optically clear or empty Nuclei imparts an optically clear or empty appearance (ground glass or Orphan Annie appearance (ground glass or Orphan Annie eye)eye)

Presence of psammoma bodiesPresence of psammoma bodies Lymphatic invasionLymphatic invasion

Follicular CarcinomaFollicular Carcinoma

Peak incidence : 40’s and 50’sPeak incidence : 40’s and 50’s Increased in areas of dietary iodine Increased in areas of dietary iodine

deficiencydeficiency High frequency of High frequency of RASRAS mutations mutations Composed of fairly uniform cells forming Composed of fairly uniform cells forming

small follicles containing colloidsmall follicles containing colloid Vascular invasion is commonVascular invasion is common

Medullary CarcinomaMedullary Carcinoma

Neuroendocrine neoplasms derived from Neuroendocrine neoplasms derived from parafollicular cells or C cells of the thyroid (calcitonin)parafollicular cells or C cells of the thyroid (calcitonin)

Component of MEN syndrome 2A or 2BComponent of MEN syndrome 2A or 2B Bilaterality and multicentricity are commonBilaterality and multicentricity are common Composed of polygonal to spindle shaped cells Composed of polygonal to spindle shaped cells

forming nests, trabeculae, and even folliclesforming nests, trabeculae, and even follicles Amyloid deposits are present in the adjacent stromaAmyloid deposits are present in the adjacent stroma Presence of multicentric C-cell hyperplasiaPresence of multicentric C-cell hyperplasia

Anaplastic CarcinomaAnaplastic Carcinoma

Undifferentiated tumors of the thyroid Undifferentiated tumors of the thyroid follicular epitheliumfollicular epithelium

Composed of highly anaplastic cellsComposed of highly anaplastic cells– Large pleomorphic giant cells (osteoclast-like Large pleomorphic giant cells (osteoclast-like

multinucleated giant cells)multinucleated giant cells)– Spindle cells with a sarcomatous appearanceSpindle cells with a sarcomatous appearance– Mixed spindle and giant cellsMixed spindle and giant cells– Small cells resembling those of small cell CaSmall cells resembling those of small cell Ca

Congenital AnomaliesCongenital Anomalies

Thyroglossal duct or cystThyroglossal duct or cyst Most commonMost common A persistent sinus tract may remain as a vestigial remnant of A persistent sinus tract may remain as a vestigial remnant of

the tubular development of the thyroid glandthe tubular development of the thyroid gland Occur at any age and manifest until adult lifeOccur at any age and manifest until adult life Cysts contains mucinous, or clear secretions and rarely over 2-Cysts contains mucinous, or clear secretions and rarely over 2-

3 cm in diameter3 cm in diameter Present in the midline of the neck anterior to the tracheaPresent in the midline of the neck anterior to the trachea Lined by stratified squamous epithelium and subjacent to this is Lined by stratified squamous epithelium and subjacent to this is

an intense lymphocytic infiltratean intense lymphocytic infiltrate Superimposed infection may occur (abscess cavities), and Superimposed infection may occur (abscess cavities), and

rarely give rise to cancersrarely give rise to cancers

PARATHYROID GLANDSPARATHYROID GLANDS

WEIGHS 35-40 MGWEIGHS 35-40 MG Yellow-brown, ovoid encapsulated noduleYellow-brown, ovoid encapsulated nodule Most are composed of chief cells; contain Most are composed of chief cells; contain

PTHPTH Activity is controlled by the level of free Activity is controlled by the level of free

(ionized) calcium(ionized) calcium

Primary HyperparathyroidismPrimary Hyperparathyroidism

Causes hypercalcemiaCauses hypercalcemia Adenoma – 75-80%Adenoma – 75-80% Primary hyperplasia (diffuse or nodular) 10-Primary hyperplasia (diffuse or nodular) 10-

15%15% Parathyroid carcinoma - <5%Parathyroid carcinoma - <5% Associated with MEN 1 & 2, Familial Associated with MEN 1 & 2, Familial

hypocalciuric hypercalcemia (FHH)hypocalciuric hypercalcemia (FHH) Skeletal changes : osteitis fibrosa cysticaSkeletal changes : osteitis fibrosa cystica

Symptomatic Primary Symptomatic Primary HyperparathyroidismHyperparathyroidism

Bone disease Bone disease NephrolithiasisNephrolithiasis GIT disturbances – constipation, nausea, peptic GIT disturbances – constipation, nausea, peptic

ulcers, pancreatitis, gallstonesulcers, pancreatitis, gallstones CNS alterations – depression, lethargy, seizuresCNS alterations – depression, lethargy, seizures Neuromuscular abnormalities – weakness and Neuromuscular abnormalities – weakness and

fatiguefatigue Cardiac manifestations – aortic or mitral valve Cardiac manifestations – aortic or mitral valve

calcificationscalcifications

Secondary HyperparathyroidismSecondary Hyperparathyroidism

Most common cause is RENAL FAILUREMost common cause is RENAL FAILURE Others : inadequate dietary calcium, Others : inadequate dietary calcium,

steatorrhea, Vitamin D deficiencysteatorrhea, Vitamin D deficiency Glands are hyperplastic with increased Glands are hyperplastic with increased

number of chief cells or cells with abundant, number of chief cells or cells with abundant, clear cytoplasm (clear-water cells)clear cytoplasm (clear-water cells)

Bone changes similar to primary typeBone changes similar to primary type Metastatic calcification may be seen in Metastatic calcification may be seen in

many tissuesmany tissues

HypoparathyroidismHypoparathyroidism

Surgically inducedSurgically induced Congenital absenceCongenital absence Familial hypothyroidismFamilial hypothyroidism

– Associated with chronic mucocutaneous Associated with chronic mucocutaneous candidiasis and primary adrenal insufficiencycandidiasis and primary adrenal insufficiency

– Known as autoimmune polyendocrine syndrome Known as autoimmune polyendocrine syndrome type I (APS I)type I (APS I)

– Mutations in the autoimmune regulator (AIRE) Mutations in the autoimmune regulator (AIRE) genegene

Idiopathic hypothyroidismIdiopathic hypothyroidism

HypoparathyroidismHypoparathyroidism

Clinical presentationsClinical presentations

Tetany – neuromuscular irritabilityTetany – neuromuscular irritability Mental status changes emotional instability, anxiety, and Mental status changes emotional instability, anxiety, and

depression, confusional states, hallucinations and psychosisdepression, confusional states, hallucinations and psychosis Intracranial manifestations – calcification of the basal ganglia, Intracranial manifestations – calcification of the basal ganglia,

parkinson-like movement disorders, increase ICPparkinson-like movement disorders, increase ICP Ocular disease – cataract formationOcular disease – cataract formation CV manifestations prolongation of QT intervalCV manifestations prolongation of QT interval Dental abnormalities – dental hypoplasia, failure of dental Dental abnormalities – dental hypoplasia, failure of dental

eruption, defective enamel and root formation, abraded carious eruption, defective enamel and root formation, abraded carious teethteeth

PseudohypoparathyroidismPseudohypoparathyroidism

End-organ unresponsiveness to PTHEnd-organ unresponsiveness to PTH Serum PTH levels are normal or elevatedSerum PTH levels are normal or elevated Pseudohypoparathyroidism Type IAPseudohypoparathyroidism Type IA

Associated with multihormone resistance (PTH, TSH, & Associated with multihormone resistance (PTH, TSH, & FSH/LH) and Albright hereditary osteodystrophy (AHO)FSH/LH) and Albright hereditary osteodystrophy (AHO)

Short stature, obesity, short metacarpal and metatarsal bones, Short stature, obesity, short metacarpal and metatarsal bones, and variable mental deficitsand variable mental deficits

Hypocalcemia, hyperphosphatemia, and elevated circulating Hypocalcemia, hyperphosphatemia, and elevated circulating PTHPTH

TSH resistance is mild; LH/FSH resistance manifests as TSH resistance is mild; LH/FSH resistance manifests as hypogonadotrophic hypogonadism in femaleshypogonadotrophic hypogonadism in females

Mutation is inherited on the maternal alleleMutation is inherited on the maternal allele

PseudohypoparathyroidismPseudohypoparathyroidism

PseudopseudohypoparathyroidismPseudopseudohypoparathyroidism Mutation is inherited on the paternal alleleMutation is inherited on the paternal allele Characterized by AHO without accompanying Characterized by AHO without accompanying

multihormonal resistancemultihormonal resistance Normal serum calcium, phosphate, and PTH Normal serum calcium, phosphate, and PTH

ADRENAL GLANDSADRENAL GLANDS

4 grams4 grams Adrenal cortexAdrenal cortex

– Glucocorticoids (cortisol) – ZF + ZRGlucocorticoids (cortisol) – ZF + ZR– Mineralocorticoids (aldosterone) – ZGMineralocorticoids (aldosterone) – ZG– Sex steroids (estrogens and androgens) - ZRSex steroids (estrogens and androgens) - ZR

Adrenal medullaAdrenal medulla– Composed of chromaffin cellsComposed of chromaffin cells– catecholaminescatecholamines

Hypercortisolism (Cushing syndrome)Hypercortisolism (Cushing syndrome)

70-80% - results from primary 70-80% - results from primary hypersecretion of ACTHhypersecretion of ACTH

10-20% - primary adrenal neoplasms and 10-20% - primary adrenal neoplasms and primary cortical hyperplasiaprimary cortical hyperplasia

About 10% - ectopicAbout 10% - ectopic Cushing disease – pituitary formCushing disease – pituitary form

Hypercortisolism (Cushing syndrome)Hypercortisolism (Cushing syndrome)

Crooke hyaline change – pituitaryCrooke hyaline change – pituitary AdrenalsAdrenals

– Cortical atrophyCortical atrophy– Diffuse hyperplasia – found in 60-70% Diffuse hyperplasia – found in 60-70% – Nodular hyperplasiaNodular hyperplasia– An adenomaAn adenoma

Primary HyperaldosteronismPrimary Hyperaldosteronism Chronic excess aldosterone secretion Chronic excess aldosterone secretion

sodium retention and potassium excretion sodium retention and potassium excretion with resultant HPN and hypokalemiawith resultant HPN and hypokalemia

Causes:Causes:– Adrenocortical neoplasm – most common Adrenocortical neoplasm – most common

Conn syndrome – adult middle life; W>MConn syndrome – adult middle life; W>M

– Primary adrenocortical hyperplasia (idiopathic Primary adrenocortical hyperplasia (idiopathic hyperaldosteronism)hyperaldosteronism)

– Glucocorticoid-remediable Glucocorticoid-remediable hyperaldosteronism – familial and genetichyperaldosteronism – familial and genetic

Primary HyperaldosteronismPrimary Hyperaldosteronism

SPIRONOLACTONE BODIES – CHARACTERISTIC FEATURE OF ALDOSTERONE SECRETING ADENOMAS

Congenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia

Autosomal recessiveAutosomal recessive Results in virilizationResults in virilization Salt wastingSalt wasting 21-Hydroxylase deficiency – most common21-Hydroxylase deficiency – most common

Congenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia

MorphologyMorphology Adrenal are bilaterally hyperplastic – 10-15XAdrenal are bilaterally hyperplastic – 10-15X Adrenal cortex is thickened and nodularAdrenal cortex is thickened and nodular On cut section, the widened cortex appears brown On cut section, the widened cortex appears brown

owing to total depletion of all lipidsowing to total depletion of all lipids Hyperplasia of corticotroph (ACTH-producing) cells is Hyperplasia of corticotroph (ACTH-producing) cells is

present in the anterior pituitarypresent in the anterior pituitary

Adrenal InsufficiencyAdrenal Insufficiency

Caused by either primary adrenal disease (primary Caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the hypoadrenalism) or decreased stimulation of the adrenals owing to a deficiency of ACTH adrenals owing to a deficiency of ACTH (secondary hypoadrenalism)(secondary hypoadrenalism)

PatternsPatterns Primary acute adrenocortical insufficiency (adrenal crisis)Primary acute adrenocortical insufficiency (adrenal crisis) Primary chronic adrenocortical insufficiency (Addison disease)Primary chronic adrenocortical insufficiency (Addison disease) Secondary adrenocortical insufficiencySecondary adrenocortical insufficiency

Primary Acute Adrenocortical Primary Acute Adrenocortical InsufficiencyInsufficiency

As a crisis As a crisis gland is incapable of gland is incapable of responding responding

Patients maintained on exogenous Patients maintained on exogenous corticosteroids corticosteroids rapid withdrawal or failure rapid withdrawal or failure to increase dose when there is increase to increase dose when there is increase requirementrequirement

As a result of massive adrenal hemorrhage As a result of massive adrenal hemorrhage destruction of the adrenal cortex destruction of the adrenal cortex

Waterhouse-Friderichsen SyndromeWaterhouse-Friderichsen Syndrome

Associated with Neisseria meningitides causing Associated with Neisseria meningitides causing overwhelming bacterial infection (others : overwhelming bacterial infection (others : Pneumococci, Pseudomonas, Haemophilus, Pneumococci, Pseudomonas, Haemophilus, staphylococcusstaphylococcus

Rapidly progressive hypotension Rapidly progressive hypotension shock shock DICDIC Adrenocortical insufficiency with massive bilateral Adrenocortical insufficiency with massive bilateral

adrenal hemorrhageadrenal hemorrhage*** *** The adrenals are converted to sacs of clotted The adrenals are converted to sacs of clotted

blood virtually obscuring all underlying detail blood virtually obscuring all underlying detail

Primary Chronic Adrenocortical Primary Chronic Adrenocortical Insufficiency (Addison Disease)Insufficiency (Addison Disease)

Causes:Causes:– Autoimmune adrenalitis – 60-70% of casesAutoimmune adrenalitis – 60-70% of cases– TuberculosisTuberculosis– AIDSAIDS– Metastatic cancersMetastatic cancers

Primary Chronic Adrenocortical Primary Chronic Adrenocortical Insufficiency (Addison Disease)Insufficiency (Addison Disease)

Hyperkalemia, hyponatremia, volume Hyperkalemia, hyponatremia, volume depletion, and hypotensiondepletion, and hypotension

Hyperpigmentation of the skinHyperpigmentation of the skin GI disturbancesGI disturbances

Secondary Adrenocortical Secondary Adrenocortical InsufficiencyInsufficiency

Any disorder of the hypothalamus and pituitary – Any disorder of the hypothalamus and pituitary – metastatic cancer, infection, infarction, or metastatic cancer, infection, infarction, or irradiation that reduces the output of ACTH irradiation that reduces the output of ACTH hypoadrenalismhypoadrenalism

Absence of hyperpigmentation because Absence of hyperpigmentation because melanotropic hormone levels are lowmelanotropic hormone levels are low

Characterized by deficient cortisol and androgen Characterized by deficient cortisol and androgen output but normal or near normal aldosterone output but normal or near normal aldosterone synthesissynthesis

Adrenal cortex may be reduced to a thin ribbon Adrenal cortex may be reduced to a thin ribbon composed largely of zona glomerulosa; medulla is composed largely of zona glomerulosa; medulla is unaffected unaffected

Adrenocortical NeoplasmsAdrenocortical Neoplasms

Adrenocortical adenomasAdrenocortical adenomas Well-circumscribed nodular lesions up to 2.5 cm in diameter Well-circumscribed nodular lesions up to 2.5 cm in diameter

that expands the adrenalthat expands the adrenal Functional adenomas are associated with atrophy of the Functional adenomas are associated with atrophy of the

adjacent cortexadjacent cortex

Adrenocortical carcinomasAdrenocortical carcinomas Rare; can occur in any age including childhoodRare; can occur in any age including childhood Inherited causesInherited causes

Li-Fraumeni syndromeLi-Fraumeni syndrome Beckwith-Wiedemann syndromeBeckwith-Wiedemann syndrome

Lesions are large, invasive, and efface the native adrenal glandLesions are large, invasive, and efface the native adrenal gland

PheochromocytomaPheochromocytoma

Adrenal medulla tumors consist of chromaffin cellsAdrenal medulla tumors consist of chromaffin cells Presents with HPNPresents with HPN 10% arise in association with several familial 10% arise in association with several familial

syndromessyndromes 10% are extra-adrenal10% are extra-adrenal 10% are bilateral10% are bilateral 10% are biologically malignant10% are biologically malignant 10% arise in childhood10% arise in childhood

Pineal GlandPineal Gland

100-180mg; located between the colliculi100-180mg; located between the colliculi PineoblastomasPineoblastomas

– First 2 decades of lifeFirst 2 decades of life– Cytology similar to primitive embryonal tumorCytology similar to primitive embryonal tumor– Spread via the CSFSpread via the CSF

PineocytomasPineocytomas– Occurs in adultsOccurs in adults

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Patho Endocrine