[GSP] M.01 ENDOCRINE SYSTEM I HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS.pdf

PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS I. II. III. IV. V. VI. VII. TOPIC OUTLINE ENDOCRINE SYSTEM HYPOTHALAMUS A. CRANIOPHARYNGIOMA PITUITARY GLAND A. ANTERIOR PITUITARY B. POSTERIOR PITUITARY C. CLINICAL MANIFESTA...

PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS I. II. III. IV. V. VI. VII. TOPIC OUTLINE ENDOCRINE SYSTEM HYPOTHALAMUS A. CRANIOPHARYNGIOMA PITUITARY GLAND A. ANTERIOR PITUITARY B. POSTERIOR PITUITARY C. CLINICAL MANIFESTATIONS of PITUITARY DISEASE D. PITUITARY ADENOMA and HYPERPITUITARISM E. HYPOPITUITARISM F. POSTERIOR PITUITARY SYNDROMES THYROID GLAND A. HYPERTHYROIDISM B. HYPOTHYROIDISM C. THYROIDITIS D. GRAVES DISEASE E. DIFFUSE and MULTINODULAR GOITER F. NEOPLASMS of the THYROID G. CONGENITAL ANOMALIES PARATHYROID GLANDS A. HYPERPARATHYROIDISM B. HYPOPARATHYROIDISM CHECKPOINT APPENDICES A. CLASSIFICATION of PITUITARY ADENOMAS B. GENETIC ALTERATIONS in PITUITARY TUMORS ENDOCRINE SYSTEM Endocrine Glands o Group of organs which orchestrate a state of equilibrium among various organs of the body. Signaling is classified into three types on the basis of the distance over which the signal acts. o Autocrine ▪ Substance secreted by a cell and acting on surface receptors of the same cell. o Paracrine ▪ Substance secreted by a cell and acting on adjacent cells. o Endocrine ▪ Secretions that are distributed in the body by way of the bloodstream. Hormones FERRER | NAMUHMUH | OLARTE | SANTIAGO Secreted molecules which act on target cells distant from their sites of synthesis. o Carried by the blood from site of release to its target. Feedback Inhibition o Target tissue secretes factors that down-regulate the activity of the gland that produces the stimulating hormone. Endocrine Disease Classifications o Diseases of underproduction or overproduction of hormones. o Diseases associated with the development of mass lesions. o DR. ARLENE L. QUITASOL 21 FEBRUARY and 06 MARCH 2024 HYPOTHALAMUS Hypothalamic Suprasellar Tumors o Most commonly implicated tumors are the following. ▪ Craniopharyngiomas ▪ Gliomas CRANIOPHARYNGIOMA Thought to arise from vestigial remnants of Rathke pouch. Slow-growing tumors accounting for one to five percent of intracranial tumors. Small minority of these lesions occur within the sella, but most are suprasellar, with or without intrasellar extension. Bimodal Age Distribution o Childhood – five to 15 years. o Adulthood – 65 years or older. Clinical Manifestations o Headaches and Visual Disturbances o Growth retardation may present in children due to pituitary hypofunction and growth hormone deficiency. Abnormalities of the Wnt signaling pathway, including mutations of the gene encoding betacatenin, have been reported. Averages three-to-four centimeters in diameter; may be encapsulated and solid, but more commonly, they are cystic and sometimes multiloculated. o Excellent recurrence-free and overall survival in those less than five centimeters in diameter. o Larger lesions are more invasive, but this does not impact prognosis. Often encroach on the optic chiasm or cranial nerves, and not infrequently they bulge into the floor of the third ventricle and base of the brain. Malignant transformation of craniopharyngiomas into squamous carcinomas 1 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS is exceptionally rare and usually occurs after irradiation. Two Distinct Histologic Variants o Adamantinomatous Craniopharyngioma ▪ Most often observed in children. ▪ Contains radiologically demonstrable calcifications. o Papillary Craniopharyngioma ▪ Most often observed in adults. ▪ Calcifies only rarely. ADAMANTINOMATOUS CRANIOPHARYNGIOMA Consists of nests or cords of stratified squamous epithelium embedded in a spongy reticulum that becomes more prominent in the internal layers. Palisading of the squamous epithelium is frequently observed at the periphery. Compact lamellar keratin formation or wet keratin is a diagnostic feature of this tumor. Dystrophic calcification is a frequent finding. Additional features include the following. o Cyst Formation o Fibrosis o Chronic Inflammation Cysts often contain cholesterol-rich, thick brownish-yellow fluid that has been compared to machine oil. Tumors extend fingerlets of epithelium into adjacent brain, where they elicit a brisk glial reaction. Right half demonstrates characteristic compact lamellar wet keratin; cords of squamous epithelium with peripheral palisading on the left. PAPILLARY CRANIOPHARYNGIOMA Contain both solid sheets and papillae lined by well-differentiated squamous epithelium. Usually lack keratin, calcification, and cysts. Squamous cells of the solid sections of the tumor lack the peripheral palisading and do not typically generate a spongy reticulum in the internal layers. FERRER | NAMUHMUH | OLARTE | SANTIAGO PITUITARY GLAND Small Bean-Shaped Structure Lies at the base of the brain within the sella turcica. Function controlled by the hypothalamus connected by a stalk containing axons extending from the hypothalamus and a rich venous plexus. Central Role o Regulates function of most other endocrine glands. Composed of two morphologically and functionally distinct components. o Anterior Lobe or Adenohypophysis o Posterior Lobe or Neurohypophysis ANTERIOR PITUITARY Constitutes about 80 percent of the gland. Produces trophic hormones that stimulate the production of hormones from the thyroid, adrenal, and other glands. Composed of epithelial cells derived embryologically from the developing oral cavity. Routine Histologic Sections o Eosinophilic cytoplasm – acidophil. o Basophilic cytoplasm – basophil. o Poorly-staining cytoplasm – chromophobe. Six Terminally-Differentiated Cell Types o Somatotrophs ▪ Growth Hormone o Mammosomatotrophs ▪ Growth Hormone ▪ Prolactin o Lactotrophs ▪ Prolactin o Corticotrophs ▪ Adrenocorticotropic Hormone ▪ Proopiomelanocortin ▪ Melanocyte-Stimulating Hormone o Thyrotrophs ▪ Thyroid-Stimulating Hormone o Gonadotrophs ▪ Follicle-Stimulating Hormone Stimulates formation of graafian follicles in the ovary. ▪ Luteinizing Hormone Induces ovulation and the formation of corpora lutea in the ovary. ▪ Same two hormones also regulate spermatogenesis and 2 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS testosterone production in males. The gland is populated by several distinct cell populations containing a variety of stimulating tropic hormones. Each hormone has different staining characteristics, resulting in a mixture of cell types in routine histologic preparations. Immunostain for human growth hormone. Specific transcription factors have been identified that regulate the differentiation of pluripotent stem cells within the Rathke’s pouch into the terminally differentiated cell types. o PIT-1 ▪ Pituitary transcription factor expressed by stem cells. ▪ Somatotrophs, mammosomatotrophs, thyrotrophs, and lactotrophs are derived from a common precursor expressing the transcription factor. o Steroidogenic Factor-1 and GATA-2 ▪ Required for gonadotroph differentiation. o Transcription Factor TPIT ▪ Also known as T-box protein 19. ▪ Corticotrophs are derived from progenitor cells expressing the transcription factor. POSTERIOR PITUITARY Consists of the following. o Modified glial cells termed as pituicytes. o Axonal processes extending from the hypothalamus through the pituitary stalk FERRER | NAMUHMUH | OLARTE | SANTIAGO to the posterior lobe termed as axon terminals. Two peptide hormones secreted, which are synthesized in the hypothalamus and stored within the axon terminals residing in the posterior pituitary. o Oxytocin ▪ Leads to contraction of the uterine smooth muscle, facilitating parturition or uterine labor. ▪ Released on nipple stimulation in the postnatal period acts on the smooth muscles surrounding the lactiferous ducts of the mammary glands and facilitates lactation. o Antidiuretic Hormone or Arginine Vasopressin ▪ Most Important Function Conserves water by restricting diuresis during periods of dehydration and hypovolemia. ▪ Stimulation of Release Decreased blood pressure, sensed by baroreceptors in the cardiac atria and carotids. Increase in plasma osmotic pressure detected by osmoreceptors. ▪ Inhibition of Secretion States of Hypervolemia Increased Atrial Distention CLINICAL MANIFESTATIONS of PITUITARY DISEASE The manifestations of pituitary disorders are related to either excess or deficiency of pituitary hormones, or to mass effects. Diseases of the posterior pituitary often come to clinical attention because of increased or decreased secretion of antidiuretic hormone and associated changes in fluid and electrolyte balances. HYPERPITUITARISM Excess secretion of trophic hormones. Causes include the following. o Pituitary Adenoma 3 | 33 PCCSOM 2026 o o o GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Hyperplasia and carcinomas of the anterior pituitary. Secretion of hormones by non-pituitary tumors. Certain Hypothalamic Disorders HYPOPITUITARISM Deficiency of trophic hormones. Caused by the following. o Ischemic Injury o Surgery or Radiation o Inflammatory Reactions o Non-Functional Pituitary Adenomas LOCAL MASS EFFECT Bitemporal Hemianopsia o Visual field abnormalities, classically in the form of defects in both lateral or temporal visual fields. o Due to the close proximity of the optic nerves and chiasm to the sella, expanding pituitary lesions often compress decussating fibers in the optic chiasm. Elevated Intracranial Pressure Signs and Symptoms o Headache o Nausea and Vomiting Pituitary Apoplexy o Acute hemorrhage into an adenoma. o Associated with clinical evidence of rapid enlargement of the lesion. o Neurosurgical emergency, as it can cause sudden death. PITUITARY ADENOMA Most common cause of hyperpituitarism. Classified on the basis of the hormones and the cell type-specific transcription factors that are expressed by the tumor cells. Some pituitary adenomas can secrete two hormones – growth hormone and prolactin being the most common combination; rarely, pituitary adenomas are plurihormonal. Classification of Pituitary Adenomas. o See appendix A. Hyperpituitarism o Less Common Causes ▪ Pituitary Carcinomas ▪ Some Hypothalamic Disorders o Large pituitary adenomas, and particularly non-functioning ones, may cause hypopituitarism by encroaching on and destroying the adjacent anterior pituitary parenchyma. FERRER | NAMUHMUH | OLARTE | SANTIAGO Usually found in adults. o Peak incidence – 35 to 65 years of age. Microadenomas – less than one centimeter in diameter. Macroadenomas – exceed one centimeter in diameter. Non-Functional Adenomas o Likely to come to clinical attention at a later stage than those associated with endocrine abnormalities. o More likely to be macroadenomas. Prevalence o Estimated to be about 14 percent. o Vast majority of these lesions are clinically-silent microadenomas or pituitary incidentalomas. Pathogenesis o Activating mutations of ubiquitinspecific protease 8. ▪ Occur in 30 to 60 percent of corticotroph adenomas. o Approximately five percent caused by germline loss-of-function mutations. ▪ MEN1 ▪ CDKN1B ▪ PRKAR1A ▪ AIP o Genetic Alterations in Pituitary Tumors ▪ See appendix B. Morphology o Soft and Well-Circumscribed o Small Adenomas ▪ Confined to the sella turcica. ▪ With expansion, they frequently erode the sella turcica and anterior clinoid process. o Larger Lesions ▪ Extend superiorly through the diaphragm sella into the suprasellar region, where they often compress the optic chiasm and adjacent structures. o 30 percent of cases are not grossly encapsulated and infiltrate neighboring tissues – aggressive adenomas. o Macroadenomas ▪ More invasive than smaller tumors and have foci of hemorrhage and necrosis. 4 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Massive, non-functional adenoma has grown beyond the confines of the sella turcica, distorting the overlying brain. On average, non-functional adenomas are larger at time of diagnosis. Histology o Uniform or monomorphic polygonal cells arrayed in sheets or cords. o Supporting connective tissue or reticulin, is sparse, accounting for the soft gelatinous consistency. o Immunohistochemical stains for hormones and lineage-specific transcription factors are used to identify specific pituitary adenoma subtypes. o Mitotic activity is usually sparse. o Cytoplasm depends on the type and amount of secretory product within the cells, but it is generally uniform throughout the tumor. ▪ Acidophilic ▪ Basophilic ▪ Chromophobic Cellular monomorphism and absence of a significant reticulin network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma. Mitotic activity and expression of Ki-67 or MIB-I, a marker of cycling cells. o Typically low in pituitary adenomas o Higher-than-normal rates of cell division are associated with more aggressive tumors. o Monomorphism of these cells contrasts markedly with the mixture of cells seen in the normal anterior pituitary. Note also the absence of reticulin network. FERRER | NAMUHMUH | OLARTE | SANTIAGO LACTOTROPH ADENOMA Prolactin-Secreting Lactotrophs Adenomas o Most frequent type of hyperfunctioning pituitary adenoma. o 30 percent of all clinically-recognized cases. o Range from small microadenomas to large expansile tumors associated with substantial mass effect. Morphology o Sparsely-Granulated Lactotroph Adenomas ▪ Large Majority ▪ Chromophobic cells with juxtanuclear localization of the transcription factor PIT-1. Sparsely granulated prolactinoma. The tumor cells contain abundant granular endoplasmic reticulum – indicative of active protein synthesis – and small numbers of electron-dense secretory granules. Acidophilic Densely-Granulated Lactotroph Adenomas ▪ Much rarer. ▪ Diffuse Cytoplasmic PIT-1 Expression Localization ▪ o ▪ Densely granulated growth hormone–secreting adenoma. The tumor cells are filled with 5 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS numerous large, electron-dense secretory granules. o Prolactin can be demonstrated within cytoplasmic secretory granules with immunohistochemical stains, and estrogen receptor alpha is co-expressed along with PIT-1, consistent with lactotroph differentiation. o Propensity to undergo dystrophic calcification, ranging from isolated psammoma bodies to extensive calcification of virtually the entire tumor mass, termed as pituitary stones. o Prolactin secretion by functioning adenomas is usually efficient and proportional. ▪ Serum prolactin concentrations tend to correlate with the size of the adenoma. Clinical Course o Increased serum levels of prolactin – termed as prolactinemia – causes the following. ▪ Amenorrhea ▪ Galactorrhea ▪ Loss of Libido ▪ Infertility o Diagnosis ▪ Made more readily in women than in men, especially between the ages of 20 and 40 years. o Hyperprolactinemia ▪ Pathologic Hyperprolactinemia Lactotroph hyperplasia caused by loss of dopamine-mediated inhibition of prolactin secretion. o Damage of the dopaminergic neurons of the hypothalamus. o Damage of the pituitary stalk, as seen in head trauma. o Exposure to drugs that block dopamine receptors on lactotroph cells. ▪ Other Causes Renal Failure Hypothyroidism Treatment o Surgery FERRER | NAMUHMUH | OLARTE | SANTIAGO o Bromocriptine ▪ Dopamine receptor agonist that causes lesions to diminish in size. SOMATOTROPH ADENOMA Second most common type of functioning pituitary adenoma. Causes the following. o Gigantism in children. o Acromegaly in adults. Quite large by the time they come to clinical attention because the manifestations of excessive growth hormone may be subtle. Histology o Pure somatotroph adenomas are classified into the following. ▪ Densely-Granulated ▪ Sparsely-Granulated o Densely-Granulated Somatotroph Adenomas ▪ Composed of monomorphic eosinophilic cells with granular cytoplasm and a large central nucleus with prominent nucleoli. ▪ Cells have a diffuse strong immunoreactivity for growth hormone. o Sparsely-Granulated Variants ▪ Composed of chromophobe cells with patchy weak-staining for growth hormone. ▪ Characteristic paranuclear glossy inclusion known as a fibrous body, composed of intermediate filaments that stain for cytokeratin. Clinical Course o Persistently elevated levels of growth hormone stimulate the hepatic secretion of insulin-like growth factor-1, which causes many of the clinical manifestations. Gigantism o Appears in children before the epiphyses have closed. o Result from elevated levels of growth hormone and insulin-like growth factor1. o Generalized increase in body size with disproportionately long arms and legs. Acromegaly o Increased levels of growth hormone after closure of epiphyses. o Growth most conspicuous in skin and soft tissues; viscera such as in the 6 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS thyroid, heart, liver, and adrenals; and the bones of the face, hands, and feet. o Bone density may increase – termed as hyperostosis – in both the spine and hips. o Enlargement of the jaw results in its protrusion – termed as prognathism – and broadening of the lower face. o Feet and hands are enlarged, and the fingers become thickened and sausagelike. Growth hormone excess can also be associated with a variety of other disturbances. o Gonadal Dysfunction o Diabetes Mellitus o Generalized Muscle Weakness o Hypertension o Arthritis o Congestive Heart Failure o Increased risk of gastrointestinal cancers. Diagnosis o Elevated serum growth hormone and insulin-like growth factor-1 levels. o Failure to suppress growth hormone production in response to an oral load of glucose. ▪ One of the most sensitive tests for acromegaly. Treatment o Removed surgically. o Treatment via pharmacologic means. ▪ Somatostatin Analogs Somatostatin inhibits pituitary growth hormone secretion. ▪ Growth Hormone Receptor Antagonists Prevent hormone binding to target organs such as the liver. ▪ Effective control of high growth hormone levels. Characteristic tissue overgrowth and related symptoms gradually recede, and the metabolic abnormalities improve. CORTICOTROPH ADENOMA Functioning Corticotroph Adenomas o Excess production of adrenocorticotropic hormone. ▪ Leads to adrenal hypersecretion of cortisol and the development FERRER | NAMUHMUH | OLARTE | SANTIAGO of hypercortisolism, also known as Cushing syndrome. Morphology o Usually microadenomas at the time of diagnosis. o Most often basophilic or denselygranulated and occasionally chromophobic or sparsely-granulated. ▪ Both variants stain positively with periodic acid-Schiff because of the presence of carbohydrate in proopiomelanocortin, the precursor of adrenocorticotropic hormone. o Nuclear TPIT is also positive in neoplastic cells, consistent with corticotroph lineage. o Crooke-Cell Adenoma ▪ Third Uncommon Variant ▪ Characterized by ringlike deposition of cytokeratin called Crooke change. ▪ Aggressive natural history compared with other subtypes of corticotroph adenomas. Clinical Course o Cushing Disease ▪ Hypercortisolism is due to excessive production of adrenocorticotropic hormone by the pituitary. o Nelson Syndrome ▪ Large destructive pituitary adenomas can develop in patients after surgical removal of the adrenal glands for the treatment of Cushing syndrome. ▪ Patients present with mass effects due to the pituitary tumor. ▪ Hyperpigmentation because of the stimulatory effects of other products of the adrenocorticotropic hormone precursor molecule on melanocytes. OTHER ANTERIOR PITUITARY TUMORS Gonadotroph (LH-Producing and FSHProducing) Adenoma o Non-Functioning Adenomas o Most frequently found in middle-aged men and women. o Can cause neurologic symptoms when they become large enough, such as 7 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS impaired vision, headaches, diplopia, or pituitary apoplexy. o Pituitary hormone deficiencies can also be found, most commonly impaired secretion of luteinizing hormone, which causes the following. ▪ Decreased energy and libido in men, due to reduced testosterone. ▪ Amenorrhea in premenopausal women. o Follicle-stimulating hormone is usually the predominant secreted hormone. o Immunoreactivity for the common gonadotropin α-subunit and the specific β-FSH and β-LH subunits. o Express steroidogenic factor-1 and GATA-2. ▪ Associated with normal gonadotroph differentiation. Thyrotroph (TSH-Producing) Adenoma o Uncommon – accounting for approximately one percent of all pituitary adenomas. o Rare cause of hyperthyroidism. o Also express PIT-1. Plurihormonal Adenoma o Secrete multiple hormones. o Usually aggressive. o Most are derived from cells of PIT-1expressing lineage. Null-Cell Adenoma o Do not express any markers of hormonal or lineage differentiation. o Typically present with symptoms stemming from mass effects. o May also compromise the residual anterior pituitary and cause hypopituitarism. Pituitary Carcinoma o Rare, accounting for less than one percent of pituitary tumors. o Presence of craniospinal or systemic metastases. o Most are functional. o Prolactin and adrenocorticotropic hormone being the most common secreted products. o Metastases usually appear late in the course, following multiple local recurrences. Pituitary Blastoma o Occurs in children, typically younger than two years of age. FERRER | NAMUHMUH | OLARTE | SANTIAGO o o o o Carry germline mutations of DICER1, the gene encoding a microRNA processing protein. Composed of immature blastema-like cells – so-called small round blue cells – and rosette-like formations resembling the primitive Rathke epithelium from which the pituitary develops. Presents with signs and symptoms of Cushing disease. Also develop primitive blastema-like neoplasms in other organs, most commonly pleuropulmonary blastoma. HYPOPITUITARISM Decreased secretion of pituitary hormones. Can result from diseases of the hypothalamus or of the pituitary. Hypofunction of the anterior pituitary occurs when approximately 75 percent of the parenchyma is lost or absent. Evidence of posterior pituitary dysfunction in the form of diabetes insipidus is almost always of hypothalamic origin. Most cases arise from destructive processes directly involving the anterior pituitary. TUMORS and OTHER MASS LESIONS Pituitary adenomas, other benign tumors arising within the sella, primary and metastatic malignancies, and cysts. Mass lesion in the sella can cause damage by exerting pressure on adjacent normal pituitary cells. TRAUMATIC BRAIN INJURY and SUBARACHNOID HEMORRHAGE Most common causes of pituitary hypofunction. PITUITARY SURGERY or RADIATION Surgical excision of a pituitary adenoma may inadvertently include the non-adenomatous pituitary. Radiation of the pituitary, used to prevent regrowth of residual tumor after surgery, can damage the non-adenomatous pituitary. PITUITARY APOPLEXY Caused by a sudden hemorrhage into the pituitary gland, often occurring into a pituitary adenoma. 8 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Abrupt onset of excruciating headache, diplopia due to pressure on the oculomotor nerves, and acute hypopituitarism. In severe cases, it can cause cardiovascular collapse, loss of consciousness, and even sudden death. Combination of mass effect from the hemorrhage and acute hypopituitarism makes pituitary apoplexy a neurosurgical emergency. SHEEHAN SYNDROME Also known as postpartum necrosis of the anterior pituitary. Most common form of clinically-significant ischemic necrosis of the anterior pituitary. Any further reduction in blood supply caused by obstetric hemorrhage or shock may precipitate infarction of the anterior lobe. Because the posterior pituitary receives its blood directly from arterial branches, it is much less susceptible to ischemic injury and is therefore usually not affected. Pituitary necrosis may also be encountered in other conditions. o Disseminated Intravascular Coagulation o Sickle-cell anemia – more rarely. o Elevated Intracranial Pressure o Traumatic Injury o Shock of any origin. RATHKE CLEFT CYST Lined by ciliated cuboidal epithelium with occasional goblet cells and anterior pituitary cells. Can accumulate proteinaceous fluid and expand, compromising the normal gland. EMPTY-SELLA SYNDROME Any condition or treatment that destroys part or all of the pituitary gland, such as ablation of the pituitary by surgery or radiation. Two Types o Primary Empty Sella ▪ Defect in the diaphragma sella allows the arachnoid mater and cerebrospinal fluid to herniate into the sella, expanding the sella and compressing the pituitary. ▪ Occurs in obese women with a history of multiple pregnancies. ▪ Affected individuals often present with visual field defects and occasionally with endocrine anomalies, such as FERRER | NAMUHMUH | OLARTE | SANTIAGO o hyperprolactinemia, due to interruption of inhibitory hypothalamic inputs. Secondary Empty Sella ▪ A mass enlarges the sella then either surgically removed or undergoes infarction, leading to loss of pituitary function. HYPOTHALAMIC LESIONS Affect the pituitary by interfering with the delivery of pituitary hormone-releasing factors. In contrast to diseases that involve the pituitary directly, hypothalamic abnormalities can also diminish the secretion of antidiuretic hormone, resulting in diabetes insipidus. Hypothalamic insufficiency can also appear following irradiation of brain or nasopharyngeal tumors. INFLAMMATORY DISORDERS and INFECTIONS Sarcoidosis Tuberculous Meningitis Involve the hypothalamus and cause deficiencies of anterior pituitary hormones and diabetes insipidus. GENETIC DEFECTS Congenital deficiency of transcription factors required for normal pituitary function is a rare cause of hypopituitarism. Mutation of the pituitary-specific gene PIT-1. o Results in combined pituitary hormone deficiency. o Deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. POSTERIOR PITUITARY SYNDROMES Involve antidiuretic hormone and include the following. o Diabetes Insipidus o Syndrome of Inappropriate Secretion of Antidiuretic Hormone DIABETES INSIPIDUS Antidiuretic Hormone Deficiency Characterized by excessive urination – termed as polyuria – due to an inability of the kidney to resorb water properly from the urine. May be due to the following. o Head Trauma o Tumors 9 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Inflammatory disorders of the hypothalamus and the pituitary. o Surgical Complications o Arise spontaneously – no identifiable underlying disorder. Central Diabetes Insipidus o Due to antidiuretic hormone deficiency. Nephrogenic Diabetes Insipidus o Result of renal tubular unresponsiveness to circulating antidiuretic hormone. Clinical manifestations of the two aforementioned disorders are similar. o SYNDROME of INAPPROPRIATE ANTIDIURETIC HORMONE Antidiuretic Hormone Excess Causes resorption of excessive amounts of free water, resulting in hyponatremia. Most Frequent Causes o Secretion of ectopic antidiuretic hormone by malignant neoplasms, particularly small-cell carcinoma of the lung. o Drugs that increase antidiuretic hormone secretion. o Variety of central nervous system disorders, including infections and trauma. Clinical Manifestations o Hyponatremia o Cerebral edema, and resultant neurologic dysfunction. o Although total body water is increased, blood volume remains normal, and peripheral edema does not develop. THYROID GLAND Located below and anterior to the larynx. Consists of two bulky lateral lobes connected by a relatively thin isthmus. Divided by thin fibrous septae into lobules composed of about 20 to 40 evenly dispersed follicles, lined by a cuboidal to low columnar epithelium, and filled with periodic acid—Schiffpositive thyroglobulin. Develops embryologically from an evagination of the pharyngeal epithelium that descends from the foramen cecum at the base of the tongue to its normal position in the anterior neck. Thyroid follicular epithelial cells convert thyroglobulin into thyroxine and lesser amounts of triiodothyronine. are released into the systemic circulation, where most of these peptides are reversibly bound to FERRER | NAMUHMUH | OLARTE | SANTIAGO circulating plasma proteins, such as thyroxinebinding globulin and transthyretin. Binding proteins act as a buffer that maintains the serum unbound or free triiodothyronine and thyroxine concentrations within narrow limits, while ensuring that the hormones are readily available to the tissues. In the periphery, the majority of free thyroxine is de-iodinated to triiodothyronine; the latter binds to thyroid hormone nuclear receptors in target cells with tenfold greater affinity than does thyroxine and has proportionately greater activity. Binding of thyroid hormone to its nuclear thyroid hormone receptor results in the assembly of a multiprotein hormone-receptor complex on thyroid hormone response elements in target genes, upregulating their transcription. Thyroid hormone has diverse cellular effects. o Stimulation of carbohydrate and lipid catabolism and protein synthesis in a wide range of cells. ▪ Net result is an increase in the basal metabolic rate. o Critical role in brain development in the fetus and neonate. Goitrogens o Variety of chemical agents that inhibit the function of the thyroid gland. o Suppress triiodothyronine and thyroxine synthesis, the level of thyroidstimulating hormone increases, and subsequent hyperplastic enlargement of the gland – termed as goiter – follows. o Propylthiouracil ▪ Antithyroid agent inhibits the oxidation of iodide and thus blocks the production of thyroid hormones. ▪ Inhibits the peripheral deiodination of circulating thyroxine into triiodothyronine, thus ameliorating symptoms of thyroid hormone excess. o Iodide ▪ When given in large doses to individuals with thyroid hyperfunction, blocks the release of thyroid hormones by inhibiting proteolysis of thyroglobulin. Follicles also contain a population of parafollicular cells or C cells which synthesize and secrete calcitonin. o Promotes the absorption of calcium by the skeletal system. 10 | 33 PCCSOM 2026 o GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Inhibits the resorption of bone by osteoclasts. HYPERTHYROIDISM Clinical Course o Protean o Hypermetabolic state induced by excess thyroid hormone and to overactivity of the sympathetic nervous system. ▪ As in an increase in the betaadrenergic tone. o Increase in the basal metabolic rate. ▪ Excessive levels of thyroid hormone. ▪ Skin is soft, warm, and flushed because of increased blood flow and peripheral vasodilation – adaptations which serve to increase heat loss. o Cardiac Manifestations ▪ Earliest and most consistent features. ▪ Elevated cardiac contractility and cardiac output, in response to increased peripheral oxygen requirements. ▪ Tachycardia, palpitations, and cardiomegaly are common. ▪ Arrhythmias, particularly atrial fibrillation, occur frequently and are more common in older patients. ▪ Myocardial Changes Focal Lymphocytic and Eosinophilic Infiltrates Mild Fibrosis Myofibril Fatty Change Increase in size and number of mitochondria. ▪ Congestive heart failure may develop, especially in older patients with preexisting cardiac disease. ▪ Thyrotoxic or Hyperthyroid Cardiomyopathy Reversible left ventricular dysfunction and low-output heart failure. o Overactivity of the Sympathetic Nervous System ▪ Tremor ▪ Hyperactivity ▪ Emotional Lability ▪ Anxiety FERRER | NAMUHMUH | OLARTE | SANTIAGO Inability to Concentrate Insomnia Thyroid Myopathy Proximal muscle weakness and decreased muscle mass; common. ▪ Gastrointestinal Tract Sympathetic hyperstimulation of the gut. o Hypermotility o Diarrhea o Malabsorption Ocular Changes ▪ Wide-Staring Gaze and Lid Lag Sympathetic overstimulation of the superior tarsal muscle – also known as Müller’s muscle – which functions alongside the levator palpebrae superioris muscle to raise the upper eyelid. ▪ True thyroid ophthalmopathy associated with proptosis occurs only in Graves disease. ▪ ▪ ▪ o Wide-eyed staring-gaze caused by overactivity of the sympathetic nervous system, is one feature of this disorder. In Graves disease, an important cause of hyperthyroidism, accumulation of loose connective tissue behind the orbit also adds to the protuberant appearance of the eyes. Skeletal System ▪ Osteoporosis and Increased Risk of Fractures Thyroid hormone stimulates bone resorption, increasing ▪ o 11 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS porosity of cortical bone and reducing the volume of trabecular bone. Thyroid Storm ▪ Medical Emergency ▪ Abrupt onset of severe hyperthyroidism. ▪ Occurs most commonly in patients with underlying Graves disease and probably results from an acute elevation in catecholamine levels, as might be encountered during infection, surgery, cessation of antithyroid medication, or any form of stress. ▪ Patients are often febrile and present with tachycardia out of proportion to the fever. ▪ Significant number of untreated patients die of cardiac arrhythmias. o Apathetic Hyperthyroidism ▪ Thyrotoxicosis occurring in older adults, in whom advanced age and various comorbidities blunt the typical features of thyroid hormone excess. ▪ Diagnosis often made during laboratory work-up for unexplained weight loss or worsening cardiovascular disease. Laboratory Findings o Serum Thyroid-Stimulating Hormone Concentration ▪ Most useful single screening test for hyperthyroidism. ▪ Levels are decreased even at the earliest stages, when the disease may still be subclinical. ▪ Low thyroid-stimulating hormone value accompanied by an increase in free thyroxine. ▪ Triiodothyronine Toxicosis Hyperthyroidism results predominantly from increased circulating levels of triiodothyronine. Diagnosis o Measurement of radioactive iodine uptake by the thyroid gland can help to determine the etiology. ▪ ▪ o FERRER | NAMUHMUH | OLARTE | SANTIAGO Diffusely increased uptake in the whole gland – Graves disease. Increased uptake in a solitary nodule – toxic adenoma. Decreased uptake – thyroiditis. ▪ Treatment o Beta-Blockers ▪ Control symptoms induced by increased adrenergic tone. o Thioamide ▪ An iodine solution to block the release of thyroid hormones; ▪ block new hormone synthesis; and ▪ inhibit peripheral conversion of triiodothyronine and thyroxine. o Radioiodine ▪ Incorporated into thyroid tissues, resulting in ablation of thyroid function over a period of six to 18 weeks. THYROTOXICOSIS Hypermetabolic State Caused by elevated circulating levels of free triiodothyronine and thyroxine. Hyperfunction of the thyroid gland. Hyperthyroidism is the most common cause of the thyrotoxicosis. Three most common causes are associated with hyperfunction of the gland. o Diffuse hyperplasia of the thyroid associated with Graves disease. ▪ Approximately 85 percent of cases. o Hyper-functional Multinodular Goiter o Hyper-functional Thyroid Adenoma PRIMARY HYPERTHYROIDISM Hyperthyroidism arising from an intrinsic thyroid abnormality. SECONDARY HYPERTHYROIDISM Arising from processes outside the thyroid, such as a thyroid-stimulating hormone-secreting pituitary tumor. HYPOTHYROIDISM Condition caused by a structural or functional derangement that interferes with the production of thyroid hormone. Prevalence o Overt hypothyroidism is 0.3 percent. 12 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Subclinical hypothyroidism is greater than four percent. o Increases with age. o Nearly tenfold more common in women than men. Can result from a defect anywhere in the hypothalamic-pituitary-thyroid axis. Laboratory Evaluation o Measurement of the serum thyroidstimulating hormone level. ▪ Most sensitive screening test for this disorder. ▪ Primary Hypothyroidism Thyroid-stimulating hormone level is increased in as a result of a loss of feedback inhibition of thyrotropinreleasing hormone and thyroid-stimulating hormone production by the hypothalamus and pituitary, respectively. ▪ Primary Hypothalamic or Pituitary Disease Thyroid-stimulating hormone level is not increased. o Thyroxine levels are decreased in individuals with hypothyroidism of any origin. Divisions o Primary ▪ Arises from an intrinsic abnormality in the thyroid itself. o Secondary ▪ Occurs as a result of pituitary and hypothalamic disease. PRIMARY HYPOTHYROIDISM Vast majority of cases. May be accompanied by an enlargement in the size of the thyroid gland – goiter. Can be congenital, autoimmune, or iatrogenic. Congenital Hypothyroidism o Most often the result of endemic iodine deficiency in the diet. o Other rare forms of congenital hypothyroidism include inborn errors of thyroid metabolism such as dyshormonogenetic goiter, wherein any one of the multiple steps leading to thyroid hormone synthesis may be defective. ▪ Iodide transport into thyrocytes. FERRER | NAMUHMUH | OLARTE | SANTIAGO Organification of iodine – binding of iodine to tyrosine residues of the storage protein thyroglobulin ▪ Iodotyrosine coupling to form hormonally active triiodothyronine and thyroxine. o In rare instances, there may be the following. ▪ Complete absence of thyroid parenchyma – thyroid agenesis. ▪ Gland may be greatly reduced in size – thyroid hypoplasia – due to germline mutations in genes responsible for development. Autoimmune Hypothyroidism o Most common cause of hypothyroidism in iodine-sufficient areas of the world. o Vast majority of cases of autoimmune hypothyroidism are due to Hashimoto thyroiditis. o Circulating Autoantibodies ▪ Antimicrosomal ▪ Antithyroid Peroxidase ▪ Antithyroglobulin Antibodies Found in this disorder, and thyroid is typically enlarged or goitrous. o Occur in isolation or in conjunction with autoimmune polyendocrine syndrome types I and II. Iatrogenic Hypothyroidism o Can be caused by either surgical or radiation-induced ablation. o Drugs given intentionally to decrease thyroid secretion, such as methimazole and propylthiouracil, can also cause acquired hypothyroidism, as can agents used to treat non-thyroid conditions such as lithium, p-aminosalicylic acid. ▪ o SECONDARY or CENTRAL HYPOTHYROIDISM Caused by deficiencies of thyroid-stimulating hormone or thyrotropin-releasing hormone. Any of the causes of hypopituitarism can cause central hypothyroidism. o Pituitary Tumor o Postpartum Pituitary Necrosis o Trauma o Non-Pituitary Tumors o Hypothalamic Damage ▪ Tumors ▪ Trauma ▪ Radiation ▪ Infiltrative Disease 13 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS CRETINISM Hypothyroidism that develops in infancy or early childhood. Fairly common in regions of the world where dietary iodine deficiency is endemic, such as the Himalayas, inland China, Africa, and other mountainous areas. On rare occasions, may also result from genetic defects that interfere with the biosynthesis of thyroid hormone. Clinical Features o Impaired development of the skeletal system and central nervous system. ▪ Severe Mental Retardation ▪ Short Stature ▪ Coarse Facial Features ▪ Protruding Tongue ▪ Umbilical Hernia o Severity of the mental impairment seems to be related to the time at which thyroid deficiency occurs in utero. ▪ Normally, maternal triiodothyronine and thyroxine cross the placenta and are critical for fetal brain development. Maternal thyroid deficiency before the development of the fetal thyroid gland leads to severe mental retardation. Maternal thyroid hormone deficiency later in pregnancy, after the fetal thyroid has become functional, does not affect normal brain development. MYXEDEMA Hypothyroidism developing in the older child or adult. Older children show signs and symptoms intermediate between those of the cretin and those of the adult with hypothyroidism. Marked by a slowing of physical and mental activity. Initial Symptoms o Generalized Fatigue o Apathy o Mental Sluggishness ▪ May mimic depression. Speech and intellectual functions are slowed. FERRER | NAMUHMUH | OLARTE | SANTIAGO Patients are listless, cold intolerant, and frequently overweight. Decreased sympathetic activity results in constipation and decreased sweating. Cool and pale skin because of decreased blood flow. Reduced Cardiac Output o Shortness of breath and decreased exercise capacity are two frequent complaints. Hypothyroidism promotes an atherogenic profile. o Increase in total cholesterol and lowdensity lipoprotein levels. o Contributes to the increased cardiovascular mortality in this disease. Accumulation of matrix substances such as glycosaminoglycans and hyaluronic acid in skin, subcutaneous tissue, and a number of visceral sites results in the following. o Non-Pitting Edema o Broadening and coarsening of facial features. o Enlargement of the tongue. o Deepening of the voice. THYROIDITIS Inflammation of the thyroid gland. Three Most Common and Clinically-Significant Subtypes o Hashimoto Thyroiditis o Granulomatous or de Quervain Thyroiditis o Subacute Lymphocytic Thyroiditis HASHIMOTO THYROIDITIS Autoimmune disease that results in destruction of the thyroid gland, and gradual and progressive thyroid failure. Most common cause of hypothyroidism in areas of the world where iodine levels are sufficient. Most prevalent between 45 and 65 years of age. More common in women than in men, with a female predominance of 10:1 to 20:1. Occur in children and is a major cause of nonendemic goiter in the pediatric population. Pathogenesis o Caused by a breakdown in self-tolerance to thyroid autoantigens. o Presence of circulating autoantibodies against thyroglobulin and thyroid peroxidase in the vast majority. o Inciting events have not been elucidated, but possibilities include abnormalities of 14 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS regulatory T cells, or exposure of normally sequestered thyroid antigens. o Strong genetic component. o Increased susceptibility associated with polymorphisms in immune regulationassociated genes, including cytotoxic T lymphocyte-associated antigen-4 and protein tyrosine phosphatase-22, both of which code for regulators of T-cell responses. o Susceptibility to other autoimmune diseases, such as type I diabetes, is also associated with polymorphisms in both cytotoxic T lymphocyte-associated antigen-4 and protein tyrosine phosphatase-22. Morphology o Diffusely enlarged thyroid. o Intact Capsule o Gland is well-demarcated from adjacent structures. o Cut surface is pale, yellow-tan, firm, and nodular. o Extensive infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers. o Thyroid Follicles ▪ Atrophic ▪ Lined by epithelial cells distinguished by presence of abundant eosinophilic granular cytoplasm termed Hürthle cells. Met aplastic response of the normally low cuboidal follicular epithelium to ongoing injury. o Fine-Needle Aspiration Biopsy Samples ▪ Presence of Hürthle cells in conjunction with a heterogeneous population of lymphocytes. o Classic Hashimoto Thyroiditis ▪ Interstitial connective tissue is increased and may be abundant. ▪ Unlike Reidel thyroiditis, fibrosis does not extend beyond the capsule. FERRER | NAMUHMUH | OLARTE | SANTIAGO Thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hürthle cells are also seen. Clinical Course o Painless enlargement of the thyroid. o Enlargement usually symmetric and diffuse. o Associated with some degree of hypothyroidism, in middle-aged women. o In some patients may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, leading to release of thyroid hormones – hashitoxicosis. ▪ Free triiodothyronine and thyroxine levels are elevated. ▪ Thyroid-stimulating hormone level is diminished. ▪ Radioactive iodine uptake is decreased. Increased risk of developing other autoimmune diseases. o Endocrine ▪ Type I Diabetes Mellitus ▪ Autoimmune Adrenalitis o Non-Endocrine ▪ Systemic Lupus Erythematosus ▪ Myasthenia Gravis ▪ Sjögren Syndrome Increased risk for the development of extranodal marginal zone B-cell lymphomas within the thyroid gland. o GRANULOMATOUS THYROIDITIS Also called de Quervain Thyroiditis. Occurs much less frequently than Hashimoto disease. Most common between the ages of 40 and 50. Affects women considerably more often than men – 4:1. Pathogenesis o Seasonal Incidence ▪ Occurrences peaking in the summer. 15 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Believed to be triggered by a viral infection. ▪ Upper Respiratory Tract Infection Morphology o Unilaterally or bilaterally enlarged and firm. o With an intact capsule that may adhere to surrounding structures. o On cut section firm and yellow-white, and stand out from the more rubbery, normal brown thyroid substance. o Early Stages in the Active Inflammatory Phase ▪ Scattered follicles may be disrupted and replaced by neutrophils forming microabscesses. o Different histologic stages are sometimes found in the same gland, suggesting waves of destruction over a period of time. o Later Stages ▪ More characteristic features appear in the form of aggregates of lymphocytes, activated macrophages, and plasma cells associated with collapsed and damaged thyroid follicles. ▪ Multinucleate giant cells enclose naked pools or fragments of colloid. ▪ Chronic inflammatory infiltrate and fibrosis may replace the foci of injury. o The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell, top left, and a colloid follicle, bottom right. Clinical Course o Most common cause of thyroid pain. o Variable enlargement of the thyroid. o Inflammation of the thyroid and hyperthyroidism are transient, usually o FERRER | NAMUHMUH | OLARTE | SANTIAGO diminishing in two to six weeks, even if the patient is not treated. o High serum triiodothyronine and thyroxine levels and low serum thyroidstimulating hormone levels. o However, unlike in hyperthyroid states such as Graves disease, radioactive iodine uptake is diminished. o After recovery, generally in six-to-eight weeks, normal thyroid function returns. Reidel Thyroiditis o Rare disorder characterized by extensive fibrosis involving the thyroid and contiguous neck structures. o Presence of a hard and fixed thyroid mass clinically simulates a thyroid carcinoma. o Associated with fibrosis in other sites in the body, such as the retroperitoneum. o Appears to be another manifestation of a systemic autoimmune IgG4-related disease, which is associated with fibrosis and tissue infiltration by plasma cells producing IgG4. SUBACUTE LYMPHOCYTIC PAINLESS THYROIDITIS Comes to clinical attention because of mild hyperthyroidism, goitrous enlargement of the gland, or both. Most often seen in middle-aged adults. More common in women. Postpartum Thyroiditis o Resembles painless thyroiditis. o Occurs during postpartum period in up to five percent of women. Most of the patients have circulating antithyroid peroxidase antibodies or a family history of other autoimmune disorders. Morphology o Mild Symmetric Enlargement o Microscopic Appearance ▪ Lymphocytic infiltration with large germinal centers within the thyroid parenchyma and patchy disruption and collapse of thyroid follicles. ▪ Unlike Hashimoto thyroiditis, however, fibrosis and Hürthle cell metaplasia are not prominent. Clinical Course o Mild transient hyperthyroidism, painless goiter, or both. 16 | 33 PCCSOM 2026 o GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Some patients transition from hyperthyroidism to hypothyroidism before recovery. GRAVES DISEASE Most common cause of endogenous hyperthyroidism. Graves reported in 1835 his observations of a disease characterized by violent and long continued palpitations in females associated with enlargement of the thyroid gland. Clinical Finding Triad o Hyperthyroidism associated with diffuse enlargement of the gland. o Infiltrative ophthalmopathy with resultant exophthalmos. o Localized infiltrative dermopathy, sometimes called pretibial myxedema, which is present in a minority of patients. Peak incidence between 20 and 40 years of age. Women are affected as much as 10 times more frequently than men. Pathogenesis o Autoimmune Disorder o Production of autoantibodies against multiple thyroid proteins, most importantly the thyroid-stimulating hormone receptor. o Thyroid-Stimulating Immunoglobulin ▪ Most common antibody subtype. ▪ Observed in approximately 90 percent of patients. ▪ Almost never observed in other autoimmune diseases of the thyroid. ▪ Binds to the thyroid-stimulating hormone receptor and mimics its actions, stimulating adenyl cyclase and increasing the release of thyroid hormones. Infiltrative Ophthalmopathy o Autoimmunity also plays a role in the development. o Protrusion of the eyeball – exophthalmos – is associated with increased volume of the retroorbital connective tissues and extraocular muscles. ▪ Marked infiltration of the retroorbital space by mononuclear cells, predominantly T cells. ▪ Inflammation with edema and swelling of extraocular muscles. FERRER | NAMUHMUH | OLARTE | SANTIAGO ▪ ▪ Accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate. Increased numbers of adipocytes – fatty infiltration. Morphology o Thyroid gland is symmetrically enlarged due to diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells. o Increases in weight to over 80 grams. o On cut section, parenchyma has a soft, meaty appearance resembling muscle. o Histology ▪ Follicular epithelial cells in untreated cases are tall and more crowded than usual. ▪ Crowding often results in the formation of small papillae, which project into the follicular lumen and encroach on the colloid, sometimes filling the follicles. ▪ Papillae lack fibrovascular cores, in contrast to those of papillary carcinoma. o Diffuse symmetric enlargement of the gland and a beefy deep red parenchyma. o Diffusely hyperplastic thyroid in a case of Graves disease. The follicles are lined by tall, columnar epithelium. The crowded, enlarged epithelial cells 17 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS project into the lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles, resulting in the scalloped appearance of the edges of the colloid. o Lymphoid infiltrates, consisting predominantly of T cells, along with scattered B cells and mature plasma cells, are present throughout the interstitium. o Germinal centers are common. o Preoperative therapy alters the morphology of the thyroid. ▪ Iodine Administration Causes involution of the epithelium and the accumulation of colloid by blocking thyroglobulin secretion. ▪ Antithyroid drug propylthiouracil exaggerates the epithelial hypertrophy and hyperplasia by stimulating thyroid-stimulating hormone secretion. Clinical Course o Diffuse enlargement of the thyroid is present in all cases. o Increased flow of blood through the hyperactive gland, often producing an audible bruit. o Sympathetic overactivity produces a characteristic wide, staring gaze and lid lag. The ophthalmopathy of Graves disease results in abnormal protrusion of the eyeball – exophthalmos. ▪ Exophthalmos may persist or progress despite successful treatment of the thyrotoxicosis, sometimes resulting in corneal injury. o Weak Extraocular Muscles o Infiltrative Dermopathy or Pretibial Myxedema ▪ Most common in the skin overlying the shins. ▪ Presents as scaly thickening and induration. Laboratory Findings o Elevated free triiodothyronine and thyroxine levels and depressed thyroidstimulating hormone levels. o Radioiodine scans show diffuselyincreased uptake of iodine. ▪ Due to ongoing stimulation of the thyroid follicles by thyroidstimulating immunoglobulins. FERRER | NAMUHMUH | OLARTE | SANTIAGO Treatment o Beta-Blockers o Thioamides, Radioiodine Ablation, and Thyroidectomy ▪ Measures aimed at decreasing thyroid hormone synthesis. o Surgery ▪ Used mostly in patients who have large goiters that are compressing surrounding structures. DIFFUSE and MULTINODULAR GOITER Goiter o Enlargement of the thyroid. o Caused by impaired synthesis of thyroid hormone, which is most often the result of dietary iodine deficiency. o Impairment of thyroid hormone synthesis leads to a compensatory rise in the serum thyroid-stimulating hormone level, causes hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the thyroid gland. o Compensatory increase in functional mass of the gland overcomes the hormone deficiency, ensuring a euthyroid metabolic state in most individuals. o Degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. o Divisions ▪ Diffuse Non-Toxic ▪ Multinodular DIFFUSE NON-TOXIC or SIMPLE GOITER Enlargement of the entire gland without producing nodularity. Colloid Goiter o Enlarged follicles are filled with colloid. Both with an endemic and a sporadic distribution. Endemic Goiter o Occurs in geographic areas where the soil, water, and food supply contain low levels of iodine. o Endemicity ▪ Goiters are present in more than 10 percent of the population in a given region. o Common in mountainous areas of the world, including the Andes and 18 | 33 PCCSOM 2026 o o o GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Himalayas, where iodine deficiency is widespread. Lack of iodine leads to decreased synthesis of thyroid hormone and a compensatory increase in thyroidstimulating hormone, leading to follicular cell hypertrophy and hyperplasia and goitrous enlargement. Increasing dietary iodine supplementation has decreased the frequency and severity of endemic goiter. Goitrogens ▪ Substances that interfere with thyroid hormone synthesis at some level. ▪ Vegetables belonging to the Brassicaceae or Cruciferae family such as cabbage, cauliflower, brussels sprouts, turnips, and cassava. Cassava contains a thiocyanate that inhibits iodide transport within the thyroid, worsening any possible concurrent iodine deficiency. Sporadic Goiter o Occurs less frequently than does endemic goiter. o Striking female preponderance. o Peak incidence at puberty or in youngadult life. o Can be caused by several conditions, including the ingestion of substances that interfere with thyroid hormone synthesis. Morphology o Two phases can be identified in the evolution of diffuse non-toxic goiter. ▪ Hyperplastic Phase Thyroid gland is diffusely and symmetrically enlarged. Rarely exceeds 100 to 150 grams. Follicles are lined by crowded columnar cells, which may pile up and form projections similar to those seen in Graves disease. ▪ Phase of Colloid Involution Follicular epithelium is flattened and cuboidal. FERRER | NAMUHMUH | OLARTE | SANTIAGO Colloid is abundant. MULTINODULAR GOITER Recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid. Virtually all longstanding simple goiters convert into multinodular goiters. Produce the most extreme thyroid enlargements. Same female-to-male distribution and presumably the same origins but affecting older individuals because they are late complications. Gross morphology demonstrating a coarsely nodular gland containing areas of fibrosis and cystic change. Hyperplastic nodule with compressed residual thyroid parenchyma on the periphery. Note the absence of a prominent capsule, a distinguishing feature from follicular neoplasms. Morphology o Multilobulated asymmetrically enlarged glands that can reach weights of more than 2,000 grams. o Intrathoracic or Plunging Goiter ▪ Goiter grows behind the sternum and clavicles. o On cut section, irregular nodules containing variable amounts of brown, gelatinous colloid. o Older lesions have areas of hemorrhage, fibrosis, calcification, and cystic change. o Microscopic Appearance ▪ Colloid-rich follicles lined by flattened inactive epithelium and areas of follicular 19 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS ▪ hyperplasia, accompanied by degenerative changes related to physical stress. In contrast to follicular neoplasms, a prominent capsule between the hyperplastic nodules and residual compressed thyroid parenchyma is not present. Clinical Course o Dominant clinical features of multinodular goiter are caused by mass effects. o May cause airway obstruction, dysphagia, and compression of large vessels in the neck and upper thorax – superior vena cava syndrome. o Most patients are euthyroid or have subclinical hyperthyroidism; identified only by reduced thyroid-stimulating hormone levels. o Plummer Syndrome ▪ An autonomous nodule may develop within a long-standing goiter and produce hyperthyroidism – toxic multinodular goiter. ▪ Seen in substantial minority of patients. ▪ Not accompanied by the infiltrative ophthalmopathy and dermopathy of Graves disease. o o o NEOPLASMS of the THYROID SOLITARY THYROID NODULE Palpably discrete swelling within an otherwise apparently normal thyroid gland. Four times more common in women than in men. Incidence increases throughout life. Majority are localized non-neoplastic lesions such as a dominant nodule in multinodular goiter, simple cysts, or foci of thyroiditis; or benign neoplasms such as follicular adenoma o Benign neoplasms outnumber thyroid carcinomas by a ratio of nearly 10:1. Several clinical criteria provide clues to the nature of a thyroid nodule. o Solitary nodules, in general, are more likely to be neoplastic than are multiple nodules. o Nodules in younger patients are more likely to be neoplastic than are those in older patients. FERRER | NAMUHMUH | OLARTE | SANTIAGO Nodules in males are more likely to be neoplastic than are those in females. A history of radiation treatment to the head and neck region is associated with an increased incidence of thyroid malignancy. Functional nodules that take up radioactive iodine in imaging studies – hot nodules – are much more likely to be benign than malignant. FOLLICULAR ADENOMA Discrete, solitary masses, derived from follicular epithelium. Clinically can be difficult to distinguish from dominant nodules of follicular hyperplasia or from the less common follicular carcinomas. Morphology o Solitary spherical encapsulated lesion that is demarcated from the surrounding thyroid parenchyma by a well-defined intact capsule. o Average about three centimeter in diameter, but some are much larger – greater than or equal to 10 centimeters in diameter. o In freshly resected specimens, bulging cut surface and compresses the adjacent thyroid. o Gray-white to red-brown, depending on the cellularity of the adenoma and its colloid content. o Areas of hemorrhage, fibrosis, calcification, and cystic change. Microscopic Appearance o Form uniform-appearing follicles that contain colloid. o Follicular growth pattern quite distinct from the adjacent non-neoplastic thyroid. o Little variation in cell size, cell shape, or nuclear morphology, and mitotic figures are rare. o Occasionally the neoplastic cells acquire brightly eosinophilic granular cytoplasm – oxyphil or Hürthle cell change. o Hallmark ▪ Presence of intact well-formed capsule encircling the tumor. o Extensive mitotic activity, necrosis, or high cellularity also warrants close inspection to exclude follicular carcinoma and the follicular variant of papillary carcinoma. 20 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS o Solitary, well-circumscribed nodule is seen. Well-differentiated follicles resembling normal thyroid parenchyma. Clinical Features o Unilateral painless masses that are discovered during a routine physical examination. o Radionuclide Scanning ▪ Nonfunctioning adenomas appear as cold nodules relative to the adjacent thyroid tissue. o Because of the need for evaluating capsular integrity, the definitive diagnosis of adenomas can be made only after careful histologic examination of the resected specimen. o Suspected adenomas of the thyroid are therefore removed surgically to exclude malignancy. o Follicular adenomas do not recur or metastasize and have an excellent prognosis. o THYROID CARCINOMA Rate of newly-diagnosed thyroid cancer has been rising dramatically, currently at the rate of three percent increase in incidence each year in the United States and in countries like South Korea, which has seen a veritable epidemic of thyroid cancer. Most common cause of newly diagnosed cancer in women. FERRER | NAMUHMUH | OLARTE | SANTIAGO Mortality from this disease is one of the lowest among solid tumors. Five-year survival greater than 98 percent. Major Subtypes and Frequency o Papillary thyroid carcinoma – 80 to 85 percent of cases. o Follicular carcinoma – 10 to 15 percent of cases. o Poorly-differentiated, or anaplastic or undifferentiated carcinoma – less than five percent of cases. o Medullary carcinoma – five percent of cases. Pathogenesis o Genetic Factors ▪ Distinct genetic events are involved in the pathogenesis of the four major histologic variants of thyroid cancer. ▪ Medullary carcinomas do not arise from the follicular epithelium. ▪ Genetic alterations in the three follicular cell–derived malignancies are in growth factor receptor signaling pathways. Most thyroid carcinomas are derived from thyroid follicle epithelium. o Except medullary carcinoma, which is derived from parafollicular C cells. Three precursor lesion relationships have been recognized. o Papillary microcarcinoma as a precursor to conventional papillary thyroid carcinoma. o Non-invasive thyroid neoplasm with papillary-like nuclear features as a precursor to invasive encapsulated follicular variant papillary thyroid carcinoma. o Non-functioning follicular adenoma as a precursor to follicular carcinoma. Most poorly-differentiated and anaplastic or undifferentiated carcinomas arise from welldifferentiated papillary thyroid carcinomas or follicular carcinomas, through acquisition of additional mutations. Poorly-differentiated and anaplastic or undifferentiated and medullary thyroid carcinomas are major causes of mortality from thyroid cancer. Pathogenesis o Driver Mutations ▪ Conventional Papillary Thyroid Carcinomas 21 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS ▪ Two Defining Genetic Abnormalities o Translocations that result in gene fusions of RET or NTRK. o Point mutations in BRAF. Follicular Neoplasms Associated with gain-offunction mutations in RAS. Neoplasms with RAS mutations retain expression of thyroid differentiation factors such as thyroglobulin and thyroid peroxidase; which may contribute to their follicular growth pattern. Approximately 20 to 40 percent of follicular adenomas and 30 to 50 percent of follicular carcinomas harbor RAS mutations. (2;3)(q13;p25) translocation has been described in 20 to 50 percent of follicular carcinomas and 10 percent of follicular adenomas. o Translocation creates a fusion gene composed of portions of PAX8, a paired homeobox gene that is important in thyroid development, and the peroxisome proliferator– activated receptor gene, which encodes a nuclear hormone receptor implicated in terminal FERRER | NAMUHMUH | OLARTE | SANTIAGO differentiation of thyrocytes. ▪ Poorly-Differentiated and Anaplastic or Undifferentiated Carcinomas Highly aggressive and lethal tumors can arise de novo, or, much more commonly, by dedifferentiation of a papillary or follicular thyroid carcinoma. Three recurrent genetic hits—point mutations of TP53, beta-catenin, and TERT which encodes the catalytic component of the enzyme telomerase, are essentially restricted to poorly differentiated and anaplastic carcinomas and likely have central roles in their genesis and aggressive behavior. ▪ Medullary Thyroid Carcinomas Occur in multiple endocrine neoplasia type II and are associated with germline RET mutations that lead to constitutive activation of the receptor. RET mutations are also seen in approximately one-half of non-familial sporadic medullary thyroid cancers. Environmental Factors o Major risk factor predisposing to thyroid cancer. ▪ Exposure to ionizing radiation, particularly during the first two decades of life. o Deficiency of dietary iodine and by extension an association with goiter is linked with a higher frequency of follicular carcinomas. PAPILLARY CARCINOMA Most common form of thyroid cancer. Accounting for nearly 85 percent of primary thyroid malignancies in the United States. 22 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Occur throughout life but most often between the ages of 25 and 50. Majority of thyroid carcinomas associated with previous exposure to ionizing radiation. Morphology o Solitary or Multifocal o Some tumors are well-circumscribed and even encapsulated; others infiltrate the adjacent parenchyma and have illdefined margins. o May contain areas of fibrosis and calcification and are often cystic. o Cut surface reveals papillary foci. Microscopic Appearance o Branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells. o When present, the papillae differ from those seen in areas of hyperplasia in being more complex and having dense fibrovascular cores. o Nuclei with finely dispersed chromatin and an optically clear or empty appearance, giving rise to the designation ground-glass or Orphan Annie eye nuclei. o Invaginations of the nuclear membrane may give the appearance of nuclear inclusions – pseudo-inclusions – or grooves. o Concentrically calcified structures termed psammoma bodies are often present, usually within the cores of papillae. o Foci of lymphatic invasion by tumor are often present, but involvement of blood vessels is relatively uncommon, particularly in smaller lesions. o Metastases to adjacent cervical lymph nodes occur in up to half of cases. o Well-Formed Papillae o Cells with characteristic emptyappearing nuclei, sometimes called Orphan Annie eye nuclei. Characteristic intranuclear inclusions are visible in some of the aspirated cells. Follicular Variant o Most Common Variant o Characteristic nuclear features of papillary carcinoma and an almost totally follicular architecture. Tall-Cell Variant o All columnar cells with intensely eosinophilic cytoplasm. o Occur in older individuals. o Higher frequencies of vascular invasion, extrathyroidal extension, and cervical and distant metastases than conventional papillary thyroid carcinoma. o Almost always harbor BRAF mutations, and often have RET/PTC translocations as well. o Cooccurrence of these two aberrations may contribute to the aggressive behavior. Diffuse-Sclerosing Variant o Macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures. FERRER | NAMUHMUH | OLARTE | SANTIAGO o 23 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Occurs in younger individuals, including children. o Prominent papillary growth pattern intermixed with solid areas containing nests of squamous metaplasia. o Extensive, diffuse fibrosis throughout the thyroid gland, often associated with a prominent lymphocytic infiltrate, simulating Hashimoto thyroiditis. o Lymph node metastases are present in almost all cases. o Lack BRAF mutations, but RET/PTC translocations are found in approximately one-half of cases. Papillary Microcarcinoma o Defined as an otherwise conventional papillary carcinoma less than one centimeter in size. o Incidental finding in patients undergoing surgery, and may be precursors of typical papillary carcinomas. Clinical Course o Present as asymptomatic thyroid nodules, but the first manifestation may be a mass in a cervical lymph node. o Presence of isolated cervical nodal metastases does not have a significant influence on prognosis, which is generally good. o Most are single nodules that move freely with the thyroid gland during swallowing and are not distinguishable on examination from benign nodules. o Hoarseness, dysphagia, cough, or dyspnea suggests advanced disease. o In a minority of patients, hematogenous metastases are present at the time of diagnosis, most commonly in the lung. Excellent prognosis, with a 10-year survival rate in excess of 95 percent. Prognosis is dependent on several factors. o Age ▪ In general, being less favorable among patients older than 40 years. ▪ Presence of Extrathyroidal Extension ▪ Presence of Distant Metastases o More common in women, 3:1, and present more often in older patients than do papillary carcinomas. Peak incidence is between 40 and 60 years of age. Morphology o Single nodules that may be well circumscribed or widely-infiltrative. o Sharply demarcated lesions may be exceedingly difficult to distinguish from follicular adenomas by gross examination. o Larger lesions may penetrate the capsule and infiltrate well beyond the thyroid capsule into the adjacent neck. o Gray-to-tan-to-pink on cut section and may be somewhat translucent due to the presence of large colloid-filled follicles. o Degenerative changes, such as central fibrosis and foci of calcification, are sometimes present. Microscopic Appearance o Composed of fairly uniform cells forming small follicles containing colloid, quite reminiscent of normal thyroid. o Occasional tumors are dominated by cells with abundant granular eosinophilic cytoplasm – Hürthle cell or oncocytic variant of follicular carcinoma. o Nuclei lack the features typical of papillary carcinoma, and psammoma bodies are not present. o Requires extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular and vascular invasion. o Criterion for vascular invasion is applicable only to capsular vessels and vascular spaces beyond the capsule; the presence of tumor plugs within intratumoral blood vessels has little prognostic significance. o Lymphatic spread is uncommon. FOLLICULAR CARCINOMA Five to 15 percent of primary thyroid cancers. More frequent in areas with dietary iodine deficiency, where they constitute 25 to 40 percent of thyroid cancers. FERRER | NAMUHMUH | OLARTE | SANTIAGO 24 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Minimal capsular invasion – feature of follicular carcinomas. o In contrast to minimally invasive follicular cancers, the diagnosis of carcinoma is obvious in widely-invasive follicular carcinomas, which infiltrate the thyroid parenchyma and extrathyroidal soft tissues. o Histologically, greater proportion of solid or trabecular growth pattern, less evidence of follicular differentiation, and increased mitotic activity. Clinical Course o Slowly-enlarging painless nodules. o Most frequently cold nodules. o Vascular or hematogenous dissemination is common, with metastases to bone, lungs, liver, and elsewhere. Prognosis and Treatment o Widely-invasive follicular carcinoma. ▪ Presents with systemic metastases. ▪ As many as half of affected patients succumb to their disease within 10 years. o Minimally-Invasive Follicular Carcinomas ▪ 10-year survival rate of greater than 90 percent. o Treated with total thyroidectomy followed by the administration of radioactive iodine, which can be used to identify metastases and to ablate such lesions. o o Cut surface of a follicular carcinoma with substantial replacement of the lobe of the thyroid. The tumor has a light-tan appearance and contains small foci of hemorrhage. o Few of the glandular lumens contain recognizable colloid. o Fibrous capsule, usually thin but occasionally more prominent, circumferentially surrounds the neoplastic follicles, and no capsular invasion is seen; compressed normal thyroid parenchyma is usually present external to the capsule at the top of the image. ANAPLASTIC or UNDIFFERENTIATED CARCINOMA Undifferentiated tumors of the thyroid follicular epithelium, accounting for less than five percent of thyroid tumors. Aggressive, with a mortality rate approaching 100 percent. Patients are older than those with other types of thyroid cancer, with a mean age of 65 years. FERRER | NAMUHMUH | OLARTE | SANTIAGO 25 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Approximately a quarter of patients have a past history of a well-differentiated thyroid carcinoma, and another quarter harbors a concurrent well-differentiated tumor in the resected specimen. Morphology o Composed of highly anaplastic cells, with variable morphology. ▪ Large, pleomorphic giant cells, including occasional osteoclastlike multinucleate giant cells. ▪ Spindle cells with a sarcomatous appearance. ▪ Mixed spindle and giant cells. o Foci of papillary or follicular differentiation may be present in some tumors, suggesting an origin from a better-differentiated carcinoma. o Neoplastic cells express epithelial markers like cytokeratin, but are usually negative for markers of thyroid differentiation, like thyroglobulin. Clinical Course o Present as a rapidly enlarging bulky neck mass. o In most cases, the disease has already spread beyond the thyroid capsule into adjacent neck structures or has metastasized to the lungs at the time of presentation. o Symptoms related to compression and invasion, such as dyspnea, dysphagia, hoarseness, and cough, are common. o No effective therapies, and the disease is almost uniformly fatal. MEDULLARY CARCINOMA Neuroendocrine neoplasms derived from the parafollicular cells, or C cells, of the thyroid. Account for approximately five percent of thyroid neoplasms. Serum Calcitonin o Measurement plays an important role in the diagnosis and postoperative followup of patients. About 70 percent of tumors arise sporadically. Remainder occurs in the setting of MEN syndrome 2A or 2B or as familial tumors without an associated MEN syndrome. Cases associated with MEN types 2A or 2B occur in younger patients, and may even arise during the first decade of life. Sporadic and familial medullary carcinomas are lesions of adulthood with a peak incidence in the fortieth and fiftieth decade of life. FERRER | NAMUHMUH | OLARTE | SANTIAGO Morphology o Sporadic medullary thyroid carcinomas present as a solitary nodule. o Bilaterality and multicentricity are common in familial cases. o Larger lesions often contain areas of necrosis and hemorrhage and may extend through the capsule of the thyroid. o Tumor tissue is firm, pale-gray-to-tan, and infiltrative. o Shows a solid pattern of growth and do not have connective tissue capsules. Abundant deposition of amyloid, visible here as homogeneous extracellular material, derived from calcitonin secreted by the neoplastic cells. Microscopic Appearance o Composed of polygonal to spindleshaped cells, which may form nests, trabeculae, and even follicles. o Small more anaplastic cells are present in some tumors and may be the predominant cell type. o Acellular amyloid deposits derived from calcitonin polypeptides are present in the stroma in many cases. o Calcitonin is readily demonstrable within the cytoplasm of the tumor cells as well as in the stromal amyloid by immunohistochemical methods. o As with all neuroendocrine tumors, electron microscopy reveals variable numbers of membrane-bound electrono 26 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS dense granules within the cytoplasm of the neoplastic cells. Familial Medullary Cancers o Presence of multicentric C-cell hyperplasia in the surrounding thyroid parenchyma, a feature that is usually absent in sporadic lesions, and that is believed to be a precursor lesion in familial cases. Clinical Course o Sporadic cases of medullary carcinoma come to medical attention most often as a mass in the neck, sometimes associated with dysphagia or hoarseness. o Initial Manifestations ▪ Paraneoplastic syndrome caused by the secretion of a peptide hormone such as diarrhea due to the secretion of vasoactive intestinal peptide, or Cushing syndrome due to adrenocorticotropic hormone. o Hypocalcemia is not a prominent feature, despite the presence of raised calcitonin levels. o In addition to circulating calcitonin, secretion of carcinoembryonic antigen by the neoplastic cells is a useful biomarker, especially for presurgical assessment of tumor load and in calcitonin-negative tumors. CONGENITAL ANOMALIES THYROGLOSSAL DUCT CYST Most common clinically-significant congenital anomaly of the thyroid. A sinus tract may persist as a vestige of the tubular development of the thyroid gland. o Parts of this tube may be obliterated, leaving small segments to form cysts. Occur at any age and might not become evident until adult life. Mucinous clear secretions may collect within the cysts to form either spherical masses or fusiform swellings, rarely over two-to-three centimeters in diameter, that present in the midline of the neck anterior to the trachea. Segments of the duct and cysts that occur high in the neck. o Lined by stratified squamous epithelium resembling the covering of the posterior portion of the tongue in the region of the foramen cecum. FERRER | NAMUHMUH | OLARTE | SANTIAGO Anomalies that occur in the lower neck more proximal to the thyroid gland are lined by epithelium resembling the thyroidal acinar epithelium. Subjacent to the lining epithelium – intense lymphocytic infiltrate. Superimposed infection may convert these lesions into abscess cavities, and rarely, they give rise to cancers. PARATHYROID GLANDS Four parathyroid glands, composed of two cell types – chief cells and oxyphil cells. o Chief Cells ▪ Predominating Cell ▪ Polygonal; 12 to 20 micrometers in diameter. ▪ Have central round uniform nuclei and light-to-dark pink cytoplasm. ▪ Sometimes, these cells take on a water-clear appearance due to the presence of large amounts of cytoplasmic glycogen. ▪ Secretory granules containing parathyroid hormone. o Oxyphil Cells and Transitional Oxyphils ▪ Found throughout the normal parathyroid, either singly or in small clusters. ▪ Slightly larger than chief cells; have acidophilic cytoplasm; and are tightly-packed with mitochondria. ▪ Glycogen granules are also present in these cells, but secretory granules are sparse or absent. In early infancy and childhood, the parathyroid glands are composed almost entirely of solid sheets of chief cells. Amount of stromal fat increases up to age 25, reaching a maximum of approximately 30 percent of the gland, and then plateaus. The function of the parathyroid glands is to regulate calcium homeostasis. o Activity controlled by the level of free ionized calcium in the bloodstream. o Normally, decreased levels of free calcium stimulate the synthesis and secretion of parathyroid hormone. Metabolic functions of parathyroid hormone which regulate serum calcium levels are as follows. 27 | 33 PCCSOM 2026 o o o o GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Increases renal tubular reabsorption of calcium thereby conserving free calcium. Increases the conversion of vitamin D to its active dihydroxy form in the kidneys. Increases urinary phosphate excretion, thereby lowering serum phosphate level. Augments gastrointestinal calcium absorption. HYPERPARATHYROIDISM Caused by elevated parathyroid hormone and is classified into the following. o Primary ▪ Autonomous overproduction of parathyroid hormone, usually resulting from an adenoma or hyperplasia of parathyroid tissue. o Secondary ▪ Compensatory hypersecretion of parathyroid in response to prolonged hypocalcemia, most commonly from chronic renal failure. o Tertiary ▪ Persistent hypersecretion of parathyroid hormone, even after the cause of prolonged hypocalcemia is corrected such as in renal transplantation. PRIMARY HYPERPARATHYROIDISM One of the most common endocrine disorders. An important cause of hypercalcemia. Frequency of various parathyroid lesions underlying the hyperfunction is as follows. o Adenoma – 85 to 95 percent. o Primary hyperplasia, diffuse or nodular – five to 10 percent. o Parathyroid carcinoma – one percent. Disease of adults and is more common in women than in men by a ratio of nearly 4:1. Annual incidence is now estimated to be about 25 cases per 100,000 in the United States and Europe; as many as 80 percent of patients with this condition are identified in the outpatient setting, when hypercalcemia is discovered incidentally on a serum electrolyte panel. o Most cases occur during the fifth decade of life or later. Solitary parathyroid adenoma arising sporadically is the most common cause of primary hyperparathyroidism. FERRER | NAMUHMUH | OLARTE | SANTIAGO Familial syndromes are a distant second to sporadic adenomas as causes of primary hyperparathyroidism. Genetic syndromes associated with familial parathyroid adenomas include the following. o Multiple Endocrine Neoplasia, Types I and II ▪ Caused by germline mutations of MEN1 and RET respectively. o Familial Hypocalciuric Hypercalcemia ▪ Rare autosomal dominant disorder caused by loss-offunction mutations in the parathyroid calcium-sensing receptor gene. ▪ Results in decreased sensitivity to extracellular calcium. Parathyroid Adenoma o Microscopic Appearance ▪ Composed of uniform polygonal chief cells with small centrallyplaced nuclei. ▪ At least a few nests of larger oxyphil cells are present as well; uncommonly, adenomas are composed entirely of this cell type – oxyphil adenomas. ▪ Rim of compressed nonneoplastic parathyroid tissue, generally separated by a fibrous capsule; often visible at the edge of the adenoma. ▪ Mitotic figures are rare, but it is not uncommon to find bizarre and pleomorphic nuclei. o ▪ Low-power photomicrograph of a solitary chief cell parathyroid adenoma revealing delineation from the residual gland below. 28 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS High-power detail of a chief cell parathyroid adenoma. There is slight variation in nuclear size but no anaplasia and a tendency for follicle formation. Primary Hyperplasia o May occur sporadically or as a component of MEN syndrome. o Classically, all four glands are involved and there is frequent asymmetry with apparent sparing of one or two glands, making the distinction between hyperplasia and adenoma difficult. o Microscopic Appearance ▪ Chief Cell Hyperplasia Most Common Pattern May involve the glands in a diffuse or multinodular pattern. ▪ Water-Clear Cell Hyperplasia Less Common Constituent cells contain abundant waterclear cells. Parathyroid Carcinomas o May be circumscribed lesions that are difficult to distinguish from adenomas, or they may be clearly invasive neoplasms. o Enlarged one parathyroid gland. o Consist of greyish-white irregular masses that sometimes exceed ten grams in weight o Cells are usually uniform and resemble normal parathyroid cells, and are arrayed in nodular or trabecular patterns. o Enclosed by a dense fibrous capsule. o Diagnosis of carcinoma based on cytologic detail is unreliable, and invasion of surrounding tissues and metastasis are the only reliable criteria. Morphology o Changes in the skeletal and urinary tract. o Symptomatic untreated primary hyperparathyroidism manifests with three interrelated skeletal abnormalities. ▪ Osteoporosis ▪ FERRER | NAMUHMUH | OLARTE | SANTIAGO Results in decreased bone mass, with preferential involvement of the phalanges, vertebra, and proximal femur. Increased osteoclast activity affects cortical bone – subperiosteal and endosteal surfaces – more severely than medullary bone. Dissecting Osteitis In medullary bone, osteoclasts tunnel centrally along the length of the trabeculae, creating the appearance of railroad tracks. Marrow spaces around the affected surfaces are replaced by fibrovascular tissue. Brown Tumor Bone loss predisposes to microfractures and secondary hemorrhages that elicit an influx of macrophages and an ingrowth of reparative fibrous tissue, creating a mass of reactive tissue. Brown color is the result of the vascularity, hemorrhage, and hemosiderin deposition, and it is not uncommon for the lesions to undergo cystic degeneration. Generalized Osteitis Fibrosa Cystica or von Recklinghausen Disease of Bone Hallmark of Severe Hyperparathyroidism o ▪ ▪ 29 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Increased Osteoclast Activity o Peri-trabecular Fibrosis o Cystic Brown Tumors o Parathyroid hormone-induced hypercalcemia favors nephrolithiasis as well as calcification of the renal interstitium and tubules, termed as nephrocalcinosis. o Metastatic calcification secondary to hypercalcemia may also be seen in other sites, including the stomach, lungs, myocardium, and blood vessels. Clinical Course o Asymptomatic and identified on routine blood chemistry profile. o Associated with the classic clinical manifestations of primary hyperparathyroidism. ▪ Painful Bones ▪ Renal Stones ▪ Abdominal Groans ▪ Psychic Moans o SECONDARY HYPERPARATHYROIDISM Caused by any condition that gives rise to chronic hypocalcemia, which in turn leads to compensatory overactivity of the parathyroid glands. Renal Failure o Most common cause of secondary hyperparathyroidism, although several other diseases, including inadequate dietary intake of calcium, steatorrhea, and vitamin D deficiency, may also cause this disorder. o Mechanisms are complex and not fully understood. Morphology o Parathyroid glands are hyperplastic. o Microscopic Appearance ▪ Increased number of chief cells, or cells with more abundant clear cytoplasm – so-called water-clear cells – in a diffuse or multinodular distribution. ▪ Fat cells are decreased in number. o Metastatic calcification may be seen in many tissues, including lungs, heart, stomach, and blood vessels. HYPOPARATHYROIDISM Far less common than hyperparathyroidism. FERRER | NAMUHMUH | OLARTE | SANTIAGO Acquired hypoparathyroidism is almost always an inadvertent consequence of surgery. Autoimmune Hypoparathyroidism o Autoimmune Polyendocrine Syndrome Type I ▪ Associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency. ▪ Caused by mutations in the autoimmune regulator gene. ▪ Presents in childhood with the onset of candidiasis, followed several years later by hypoparathyroidism and then adrenal insufficiency during adolescence. Autosomal-Dominant Hypoparathyroidism o Caused by gain-of-function mutations in the calcium-sensing receptor gene. o Inappropriate calcium-sensing receptor gene activity due to heightened calcium sensing suppresses parathyroid hormone, resulting in hypocalcemia and hypercalciuria. Familial-Isolated Hypoparathyroidism o Rare Condition o Either autosomal dominant or autosomal recessive pattern of inheritance. o Autosomal-Dominant Familial-Isolated Hypoparathyroidism ▪ Caused by a mutation in the gene encoding parathyroid hormone precursor peptide, which impairs its processing to the mature hormone. o Autosomal-Recessive Familial-Isolated Hypoparathyroidism ▪ Caused by loss-of-function mutations in the transcription factor gene glial cells missing-2, which is essential for development of the parathyroid. Congenital Absence of Parathyroid Glands o Can occur in conjunction with other malformations, such as thymic aplasia and cardiovascular defects, or as a component of the 22q11 deletion syndrome. o When thymic defects are present, the condition is called DiGeorge syndrome. Clinical Features o Major clinical manifestations related to the severity and chronicity of the hypocalcemia. o Hallmark of Hypocalcemia 30 | 33 PCCSOM 2026 o GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS Tetany Characterized by neuromuscular irritability. Resulting from decreased serum calcium levels. Symptoms o Circumoral numbness or paresthesia of the distal extremities and carpopedal spasm. o LifeThreatening Laryngospasm o Generalized Seizures Physical Examination Classic Findings ▪ Chvostek Sign Elicited in subclinical disease by tapping along the course of the facial nerve, which induces contractions of the muscles of the eye. ▪ Trousseau Sign Carpal spasms produced by occlusion of the circulation to the forearm and hand with a blood pressure cuff for several minutes. ▪ PSEUDOHYPOPARATHYROIDISM Hypoparathyroidism occurs because of endorgan resistance to the actions of parathyroid hormone. Serum parathyroid hormone levels are normal or elevated. In one form of pseudohypoparathyroidism, there is end-organ resistance to thyroid-stimulating, folliclestimulating, luteinizing, and parathyroid hormone. Parathyroid hormone resistance is the most obvious clinical manifestation. It presents as hypocalcemia, hyperphosphatemia, and elevated circulating parathyroid hormone. Thyroid-stimulating hormone resistance is generally mild, while luteinizing and folliclestimulating hormone resistance manifests as hypergonadotropic hypogonadism in females. FERRER | NAMUHMUH | OLARTE | SANTIAGO 1. 2. 3. 4. 5. 6. 7. 8. 9. CHECKPOINT Which histologic variant of craniopharyngioma is most often observed in adults? a. Adamantinomatous b. Papillary c. All of the above. d. None of the above. Which of the following is the most common cause of hyperpituitarism? a. Hypothalamic Disorders b. Non-Pituitary Tumors c. Anterior Pituitary Carcinoma d. Pituitary Adenoma Which of the following is the most frequent type of hyperfunctioning pituitary adenoma? a. Somatotroph b. Corticotroph c. Lactotroph d. Gonadotroph Which of the following is the most common cause of pituitary hypofunction? a. Subarachnoid Hemorrhage b. Traumatic Brain Injury c. All of the above. d. None of the above. Which of the following is the most common variant of papillary carcinoma? a. Tall-Cell b. Diffuse-Sclerosing c. Papillary Microcarcinoma d. Follicular Which of the following posterior pituitary syndromes would be due to antidiuretic hormone deficiency? a. Central Diabetes Insipidus b. Nephrogenic Diabetes Insipidus c. Syndrome of Inappropriate Antidiuretic Hormone d. None of the above. Which of the following is the most common form of clinically-significant ischemic necrosis of the anterior pituitary? a. Sheehan Syndrome b. Pituitary Apoplexy c. Rathke Cleft Cyst d. None of the above. Which gene is most commonly associated with a pituitary blastoma? a. DICER1 b. MEN1 c. CDKN1B d. HRAS Which of the following would not lead to an acute elevation of catecholamine levels and, 31 | 33 PCCSOM 2026 10. 11. 12. 13. 14. 15. 16. 17. GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS ultimately, thyroid storm in patients with Graves disease? a. Stress b. Infection c. Surgery d. None of the above. Which of the following thyroid carcinomas is not derived from thyroid follicle epithelium? a. Anaplastic b. Papillary c. Follicular d. Medullary Which of the following would have a nucleus with finely dispersed chromatin and an optically clear or empty appearance, also known as an Orphan Annie eye nucleus? a. Follicular b. Anaplastic c. Medullary d. Papillary “Anaplastic or undifferentiated carcinomas are aggressive and have a mortality rate approaching 100 percent.” a. True b. False Which parathyroid gland cell type is described as sometimes taking on a water-clear appearance? a. Chief Cells b. Oxyphil Cells c. All of the above. d. None of the above. Which classification of hyperparathyroidism is described as a compensatory hypersecretion of parathyroid in response to prolonged hypercalcemia? a. Primary b. Secondary c. Tertiary d. None of the above. Which of the following parathyroid lesions has the lowest frequency? a. Primary Hyperplasia b. Adenoma c. Parathyroid Carcinoma d. None of the above. Which of the following is the most common cause of secondary hyperparathyroidism? a. Severe Vitamin D Deficiency b. Chronic Kidney Failure c. Severe Calcium Deficiency d. None of the above. Which of the following is the inheritance pattern of familial-isolated hypoparathyroidism? a. Autosomal-Dominant b. Autosomal-Recessive c. All of the above. d. None of the above. 18. A 40-year-old man visits the physician because of weakness and easy fatigability of two-months' duration. Physical examination yields no remarkable findings. Laboratory studies show serum calcium of 11.5 mg/dL, inorganic phosphorus of 2.4 mg/dL, and serum parathyroid hormone of 58 pg/mL, which is near the top of the reference range. A radionuclide bone scan fails to show any areas of increased uptake. What is the most likely cause of these findings? a. Parathyroid Adenoma b. Parathyroid Carcinoma c. Parathyroid Hyperplasia d. Hypervitaminosis D 19. A 45-year-old woman reports a feeling of fullness in her neck, but has no other complaints. The enlargement has been gradual and painless for more than one year. Physical examination confirms diffuse enlargement of the thyroid gland without any apparent masses. Laboratory studies of thyroid function show a normal free thyroxine level and a slightly increased thyroidstimulating hormone level. What is the most likely cause of these findings? a. Toxic Multinodular Goiter b. Papillary Carcinoma c. Subacute Granulomatous Thyroiditis d. Diffuse Non-Toxic Goiter 20. A 10-year-old boy has been bothered by frequent headaches for the past five months. Physical examination yields no specific findings. Laboratory studies show normal electrolyte levels. CT scan of the head shows no bony abnormalities and no intracranial hemorrhage. MRI of the brain shows a twocentimeter solid mass without calcifications or cystic change in the area inferior to the splenium of the corpus callosum, superior to the collicular plate, and between the right and left thalamic pulvinar regions. Because of the location, the mass is difficult to remove completely. Which of the following neoplasms is most likely to be present in this child? a. Craniopharyngioma b. Metastatic Carcinoma c. Pineoblastoma d. Prolactinoma 1b2d3c4c5d6a7a8a9d10d11d12a13a14b15c16b17c18a19d20c FERRER | NAMUHMUH | OLARTE | SANTIAGO 32 | 33 PCCSOM 2026 GENERAL and SYSTEMIC PATHOLOGY M.01 ENDOCRINE SYSTEM I: HYPOTHALAMUS, PITUITARY, THYROID, and PARATHYROID GLANDS APPENDICES A. CLASSIFICATION of PITUITARY ADENOMAS B. GENETIC ALTERATIONS in PITUITARY TUMORS FERRER | NAMUHMUH | OLARTE | SANTIAGO 33 | 33