Pathology (Endocrine, pituitary, thyroid)

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Pathology (Endocrine, pituitary, thyroid)
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2013-09-08 13:47:07
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  1. What is the mcc of pineal tiumor?
    Germ cell tumor
  2. What is the origin of craniopharyngioma?
    vestigial remnants of Rathke pouch
  3. Where is the location of craniopharyngioma?
    Suprasellar
  4. What is the molecular abnormality in craniopharyngioma?
    Wnt signaling pathway
  5. What are the two subtypes of craniopharyngioma?
    adamantinomatous craniopharyngioma (most often observed in children) and papillary craniopharyngioma (most often observed in adults). The adamantinomatous type frequently contains radiologically demonstrable calcifications; the papillary variant calcifies only rarely.
  6. What are the morphological characteristics of adamantinomatous subtype of craniopharyngioma?
    • 1. nests or cords of stratified squamous epithelium embedded in a spongy “reticulum” 2. “Palisading” of the squamous epithelium at the periphery.
    • 3. Compact, lamellar keratin formation (“wet keratin”) .
    • 4. dystrophic calcification is a frequent finding.
    • 5.The cysts of adamantinomatous craniopharyngiomas often contain a cholesterol-rich, thick brownish-yellow fluid that has been compared to “machine oil.”
    • 6. brisk glial reaction.
  7. What is morphological feature of papillary craniopharyngioma?
    Papillary craniopharyngiomas contain both solid sheets and papillae lined by well-differentiated squamous epithelium. These tumors usually lack keratin, calcification, and cysts. The 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.
  8. What is the origin of Hypopituitarism accompanied by evidence of posterior pituitary dysfunction in the form of diabetes insipidus ?
    Always hypothalamus
  9. What is the mcc of pituitary apoplexy (hemorrhage)?
    Adenoma
  10. Which lobe of the pituitary undergoes necrosis in Sheehan syndrome?
    Ant. lobe (because of low pressure venous system)
  11. What is the mcc of pituitary ischemic necrosis?
    Sheehan syndrome?
  12. Why does Sheehan syndrome occur in pregnancy?
    • Pituitary enlarges but the ant lobe blood supply (low pressure veins) does not.
    • Pos.lobe is supplies by arteries and is less susceptible
  13. What are other causes of ischemic pituitary necrosis?
    DIC, Shock, SCA
  14. What is a Rathke cleft cyst?
    These cysts, lined by ciliated cuboidal epithelium with occasional goblet cells and anterior pituitary cells, can accumulate proteinaceous fluid and expand, compromising the normal gland.
  15. What is Empty sella syndrome?
    The empty sella syndrome refers to the presence of an enlarged, empty sella turcica due to any condition that destroys part or all of the pituitary gland.
  16. What is the defect in primary empty sella syndrome?
    There is a defect in the diaphragma sella that allows the arachnoid mater and cerebrospinal fluid to herniate into the sella, resulting in expansion of the sella and compression of the pituitary (obese women with multiple pregnancies)
  17. What are symptoms of the primary empty sella syndrome?
    Hyperprolactinemia, visual field defect, hypopituitarism
  18. What is secondary empty sella syndrome?
    In a secondary empty sella, a mass, such as a pituitary adenoma, enlarges the sella, but then it is either surgically removed or undergoes spontaneous necrosis, leading to loss of pituitary function. Hypopituitarism can result from the treatment or spontaneous infarction.
  19. What is the mc pitiutary adenoma?
    Lactotroph
  20. Presenting with mass effect is most likely to be seen in which pituitary adenoma?
    Gonadotroph
  21. What is the most well-studied genetic problem in pituitary adenoma? and in which adenoma it is common?
    GNAS mutation resulting in constitutive activity of GTPase activity of the alpha subunit of Gs. Somatotroph
  22. Which genetic defects are associated with an aggressive behavior in pituitary adenomas?
    cell cycle checkpoint genes, such as overexpression of cyclin D1, mutations of p53, and epigenetic silencing of the retinoblastoma gene (RB1)
  23. Which other important genes are either activated or inactivated in pituitary tumors?
    • PKA (gain of function)--> GH, PRL
    • HRAS (gain of function)--> carcinoma
    • Menin (MEN1) (loss of function)--> PRL, GH, ACTH
  24. What is the gross pathological hallmark of pituitary adenomas?
    • 1. soft, well-circumscribed
    • 2. Larger lesions extend superiorly through the diaphragm sella into the suprasellar region, and compress the optic chiasm and some of the cranial nerves.
    • 3. As these adenomas expand, they frequently erode the sella turcica and anterior clinoid processes.
    • 4. adenomas that are not grossly encapsulated and infiltrate neighboring tissues are termed invasive adenomas.
    • 5. macroadenomas more invasive, hemorrhage and necrosis
  25. What is the microscopic pathological hallmark of pituitary adenomas?
    • 1. cellular monomorphism and the absence of a significant reticulin network
    • 2. Mitotic activity is usually sparse. 
    • 3. The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic, depending on the type
    • 4. Brisk mitotic activity associated with P53+ of nucleus, Ki-67, and higher aggressive behavior
  26. What are the features of lactotroph adenomas?
    • 1. Weakly acidophilic or cromophobe
    • 2. Dystrophic calcification (pituitary stone, psammoma bodies)
    • 3. PRL correlates with size
  27. What are the other causes of hyperprolactinemia?
    • 1. Physiologic (pregnancy)--> peak at delivery, nipple stimulation, stress
    • 2. Pathologic (lactotroph hyperplasia) when there is interference with normal dopamine inhibition --> damage to the dopaminergic neurons of the hypothalamus, damage to the pituitary stalk dopamine receptor blockers on lactotroph cells, Any mass in the suprasellar compartment
    • 3. estrogens, renal failure, and hypothyroidism
  28. What are the clinical features of pituitary GH tumor?
    • Can become very large before diagnosis
    • 1. before the epiphyses have closed--> gigantism characterized by a generalized increase in body size with disproportionately long arms and legs+ acromegaly signs.
    • 2. after closure of the epiphyses--> acromegaly: growth is most conspicuous in skin and soft tissues; viscera (thyroid, heart, liver, and adrenals); and bones of the face, hands, and feet.
    • increased Bone density increased (hyperostosis) in both the spine and the hips.
    • Enlargement of the jaw results in protrusion (prognathism), with broadening of the lower face.
    • sausage-like fingers.
    • gonadal dysfunction, diabetes mellitus, generalized muscle weakness, hypertension, arthritis, congestive heart failure, and an increased risk of gastrointestinal cancers.
  29. What are the morphological features of GH tumors?
    • 1.The densely granulated adenomas are composed of cells that are monomorphic and acidophilic, retain strong cytoplasmic GH reactivity on immunohistochemistry, and demonstrate cytokeratin staining in a perinuclear distribution.
    • 2., the sparsely granulated variants are composed of chromophobe cells with considerable nuclear and cytologic pleomorphism and focal, weak staining for GH. 
    • 3. morphologically, most bihormonal adenomas resemble the densely granulated pure somatotroph adenomas.
  30. How is GH secreting tumors diagnosed?
    • 1. elevated serum GH and IGF-1 levels.
    • 2. failure to suppress GH production in response to an oral load of glucose 
  31. What are the histologic features of ACTH secreting tumors?
    • 1. Basophilic or sometimes chromophobe
    • 2. PAS+ due to presence of carbohydrate in POMC
    • 3. Positive for POMC, ACTH, beta endorphin
    • 4. Usually microadenoma
  32. What is Nelson syndrome?
    • Large destructive adenomas can develop in patients after surgical removal of the adrenal glands for treatment of Cushing syndrome. This condition, known as Nelson syndrome, occurs most often because of a loss of the inhibitory effect of adrenal corticosteroids on a preexisting corticotroph microadenoma.
    • no hypercortisolism
    • present with mass effects
    • hyperpigmentation due to MSH
  33. What are the diagnostic features of gonadotroph adenomas?
    • 1. secrete hormones inefficiently and variably
    • 2. mass effect
    • 3. hormone deficiencies most commonly impaired secretion of LH ->decreased energy and libido in men (due to reduced testosterone) and amenorrhea in premenopausal women
    • 4. FSH is usually the predominant secreted hormone.
  34. What are the morphological characteristics of thyroglossal duct cyst?
    • Segments of the duct and cysts that occur high in the neck are lined by stratified squamous epithelium 
    • The anomalies that occur in the lower neck more proximal to the thyroid gland are lined by epithelium resembling the thyroidal acinar epithelium.
    • Characteristically, subjacent to the lining epithelium, there is an intense lymphocytic infiltrate. 
  35. What is the mcc of hypothyroidism?
    Hashimoto
  36. What are the important genetic factros in Hashimoto thyroiditis?
    • cytotoxic T lymphocyte–associated antigen-4 (CTLA4) and protein tyrosine phosphatase-22 (PTPN22) polymorphisms both of which are inhibitors of T-cell
    • HLA-DR3
  37. What is the major defect in immunity of patients with autoimmune thyroiditis?
    Defect in self-tolerance
  38. How are the thyroid cells killed in Hashimoto thyroiditis?
    • CD8+ cytotoxic T cell–mediated cell death: CD8+ cytotoxic T cells may cause thyrocyte destruction.  
    • Cytokine-mediated cell death: Excessive T-cell activation leads to the production of TH1 inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant recruitment and activation of macrophages and damage to follicles.  
    • Binding of anti-thyroid antibodies (anti-thyroglobulin, and anti-thyroid peroxidase antibodies) followed by antibody-dependent cell-mediated cytotoxicity
  39. What is the morphology of Hashimoto thyroiditis?
    • 1. Diffuse enlargement, intact capsule, well demarcated gland.
    • 2. The cut surface is pale, yellowtan, firm, and somewhat nodular.
    • 3. Extensive infiltration of the parenchyma by amononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers
    • 4. The thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hürthle cells. (metaplastic) 
    • 5. In “classic” Hashimoto thyroiditis, interstitial connective tissue is increased and may be abundant.
    • 5. Unlike Reidel thyroiditis, the fibrosis does not extend beyond the capsule of the gland. 
  40. What are the clinical features of Hashimoto?
    • 1. painless symmetric diffuse enlargement of the thyroid, usually associated with some degree of hypothyroidism, in a middle-aged woman.
    • 2. It may be preceded by transient thyrotoxicosis caused by disruption of thyroid follicles, with secondary release of thyroid hormones (“hashitoxicosis”). During this phase, free T4 and T3 levels are elevated, TSH is diminished, and radioactive iodine uptake is decreased.
    • 3. As hypothyroidism supervenes, T4 and T3 levels fall, accompanied by a compensatory increase in TSH.
  41. Risk of which diseases are increased in Hashimoto thyroiditis?
    • 1. AI (DM1, adrenalitis, SLE...)
    • 2. B-cell NHL (marginal MALToma)
  42. What are the characteristics of De Quervain thyroiditis (subacute granulomatous)?
    • 1. Triggered by viral infection (coxsackie, mumps)--> URI
    • 2. More common in summer
    • 3. Release of Ag by tissue destruction--> activation of CD8 lymphocytes--> thyroid destruction
    • 4. MCC of painful thyroid
    • 5. MNGC and granuloma
    • 6. high serum T4 and T3 levels and low serum TSH levels
    • 7. Decreased RAIU
    •  
  43. What is the most common cause of thyroid pain?
    Granulomatous (de Quervain) thyroiditis 
  44. What is the mc manifestation of subacute painless thyroiditis?
    Hyperthyroidism or goiter
  45. What are the differences and similarities between SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS and Hashimoto thyroiditis?
    • Sim--> increased anti TPO, hypothyroidism in 1/3 of the patients with SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS, lymphocytic infilteration +hyperplastic germinal centers
    • Diff--> no Hurthle metaplasia or fibrosis in subsacute thyroiditis
  46. Which variant of thyroiditis occurs in postpartum women?
    SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS
  47. What are the features of Reidel's thyroiditis?
    • Extensive fibrosis involving the thyroid and contiguous neck structures.
    • The presence of a hard and fixed thyroid mass clinically simulates a thyroid carcinoma.
    • It may be associated with idiopathic fibrosis in other sites in the body, such as the retroperitoneum.
    • The presence of circulating anti-thyroid antibodies in most patients suggests an autoimmune etiology.
  48. What is the mcc of congenital hypothyroidism?
    Iodine deficiency
  49. What is the mcc of thyroid dysmorphogenesis?
    TPO deficiency
  50. What causes of hypothyroidism are associated with goiter?
    • Hashimoto thyroiditis
    • Iodine deficiency  
    • Drugs (lithium, iodides, p-aminosalicylic acid)
    • Congenital biosynthetic defect (dyshormonogenetic goiter)
  51. What causes of hypothyroidism are not associated with goiter?
    • Developmental (thyroid dysgenesisor agenesis: PAX8, FOXE1, TSH receptor mutations)  
    • Postablative  Surgery, radioiodine therapy, or external irradiation
    • Secondary hypothyroidism
  52. What are the manifestations of thyroid resistance syndrome?
    • Increased T3, T4, TSH
    • Hypothyroidism
  53. What are the antibodies seen in Hashimoto thyroiditis?
    anti-microsomal, anti-thyroid peroxidase, and anti-thyroglobulin
  54. When does maternal hypothyroidism affect fetus brain?
     If there is maternal thyroid deficiency before the development of the fetal thyroid gland, mental retardation is severe. In contrast, reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has developed, allows normal brain development.
  55. What are the clinical manifestation of cretinism?
    Impaired development of the skeletal system and central nervous system, manifested by severe mental retardation, short stature, coarse facial features, a protruding tongue, and umbilical hernia
  56. What symptoms of hypothyroidism are caused by GAG deposition?
    non-pitting edema, a broadening and coarsening of facial features, enlargement of the tongue, and deepening of the voice
  57. What is the pathophysiology of cardiac symptoms in hypothyroidism?
    • Thyroid hormones regulate the transcription of several sarcolemmal genes, such as calcium ATPases, whose encoded products are critical in maintaining efficient cardiac output.
    • In addition, hypothyroidism promotes an atherogenic profile—an increase in total cholesterol and low-density lipoprotein (LDL) levels—probably contributing toward the adverse cardiovascular mortality rates in this disease.  
    • Moreover the decrease in water clearance causes Diastolic HTN.
  58. What are the causes of thyrotoxicosis associated with hyperthyroidism?
    • Diffuse toxic hyperplasia (Graves disease)  
    • Hyperfunctioning (“toxic”) multinodular goiter  
    • Hyperfunctioning (“toxic”) adenoma  Iodine-induced hyperthyroidism  
    • Neonatal thyrotoxicosis associated with maternal Graves disease
    • Secondary
  59. What are the causes of thyrotoxicosis NOT associated with hyperthyroidism?
    • Granulomatous (de Quervain) thyroiditis (painful)  
    • Subacute lymphocytic thyroiditis (painless)  
    • Struma ovarii (ovarian teratoma with ectopic thyroid)  
    • Factitious thyrotoxicosis (exogenous thyroxine intake)
  60. What are the general causes of hyperthyroidism symptoms?
    hypermetabolic state and sympathetic overactivity
  61. What are the consequences of an increased in BMR in skin?
    • soft, warm, and flushed skin because of increased blood flow and peripheral vasodilation to increase heat loss. 
    • Heat intolerance
    • Sweating because of higher levels of calorigenesis. 
  62. What is the pathophysiology of cardiac disorder in hyperthyroidism?
    • An increase in cardiac output, due to both increased cardiac contractility and increased peripheral oxygen requirements
    • Tachycardia, palpitations, and cardiomegaly
    • Arrhythmias, particularly atrial fibrillation, especially in older patients
    • CHF may develop, particularly in elderly patients with preexisting cardiac disease.
    • Myocardial changes, such as foci of lymphocytic and eosinophilic infiltration, mild fibrosis in the interstitium, fatty changes in myofibers, and an increase in size and number of mitochondria
    • Some individuals with thyrotoxicosis develop reversible left ventricular dysfunction and “low-output” heart failure, so-called thyrotoxic or hyperthyroid cardiomyopathy.
  63. What are the changes in neuromuscular system of thyrotoxicosis?
    • Overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, and insomnia.
    • Proximal muscle weakness and decreased muscle mass are common (thyroid myopathy).
  64. Which of the ocular changes is seen in any kind of thyrotoxicosis?
    A wide, staring gaze and lid lag are present because of sympathetic overstimulation of the levator palpebrae superioris
  65. What are the manifestations of hyperthyroidism in GI?
    SNS hyperactivity causes hypermotility, malabsorption, and diarrhea
  66. What are the effects of thyrotoxicosis on the bone, liver, muscles and lymphoid system?
    • Thyroid hormone stimulates bone resorption, increasing porosity of cortical bone and reducing the volume of trabecular bone. The net effect is osteoporosis
    • Atrophy of skeletal muscle, with fatty infiltration and focal interstitial lymphocytic infiltrates
    • Minimal liver enlargement due to fatty changes in the hepatocytes
    • Generalized lymphoid hyperplasia and lymphadenopathy in patients with Graves disease.
  67. What are the prominent symptoms in patients with apathetic hyperthyroidism?
    Unexplained weight loss or worsening cardiovascular disease
  68. How can we diagnose secondary hyperthyroidism with equivocal levels of TSH?
    A normal rise in TSH after administration of TRH excludes secondary hyperthyroidism. (in TSH adenoma no increase in TSH following TRH administration is seen
  69. What is the lab in T3 toxicosis?
    Normal or reduced T4, reduced TSH, and high T3
  70. What is the triad of Grave's disease?
    • 1.   Hyperthyroidism due to diffuse, hyperfunctional enlargement of the thyroid  
    • 2.   Infiltrative ophthalmopathy with resultant exophthalmos  
    • 3.   Localized, infiltrative dermopathy, sometimes called pretibial myxedema, which is present in a minority of patients
  71. What are the genetic associated of Grave's disease?
    CTLA4 and PTPN22 and the HLA-DR3, and B8
  72. What is the most specific Ab in Grave's disease?
    TSI
  73. Which Ab is present in nearly all patients with Grave's disease?
    TSI
  74. What are the Ab seen in Grave's disease?
    • 1. Thyroid-stimulating immunoglobulin: This IgG antibody binds to the TSH receptor and mimics the action of TSH, stimulating adenyl cyclase and increasing the release of thyroid hormones.
    • 2. Thyroglobulin and thyroid peroxidase antibodies.  
    • 3. Thyroid growth-stimulating immunoglobulins: directed against the TSH receptor, it have been implicated in the proliferation of thyroid follicular epithelium. 4. TSH-binding inhibitor immunoglobulins: These anti–TSH receptor antibodies prevent TSH from binding normally to its receptor on thyroid epithelial cells, either activate it or inhibit it. (explain the episodes of hypothyroidism)
  75. What are the histological changes in thyroid ophthalmopathy?
    • (1) marked infiltration of the retro-orbital space by mononuclear cells, predominantly T cells
    • (2) inflammatory edema and swelling of extraocular muscles
    • (3) accumulation of extracellular matrix components, specifically hydrophilic glycosaminoglycans such as hyaluronic acid and chondroitin sulfate
    • (4) increased numbers of adipocytes (fatty infiltration). 
  76. What is the mechanism of thyroid ophthakmopathy?
    Orbital preadipocyte fibroblasts express the TSH receptor and thus become targets of an autoimmune attack. T cells reactive against these fibroblasts secrete cytokines, which stimulate fibroblast proliferation and synthesis of extracellular matrix proteins (glycosaminoglycans) and increase surface TSH receptor expression, perpetuating the autoimmune response. The result is progressive infiltration of the retro-orbital space and ophthalmopathy.
  77. What is the histology of thyroid in Grave's disease?
    • Symmetric enlargement because of diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells
    • On cut section, the parenchyma has a soft, meaty appearance resembling normal muscle.
    • Histologically, the follicular epithelial cells in untreated cases are tall and more crowded than usual.
    • This crowding often results in the formation of small papillae, which project into the follicular lumen and encroach on the colloid, sometimes filling the follicles
    • Such papillae lack fibrovascular cores, in contrast to those of papillary carcinoma. The colloid within the follicular lumen is pale, with scalloped margins.
    • Lymphoid infiltrates, consisting predominantly of T cells, with fewer B cells and mature plasma cells, are present throughout the interstitium; germinal centers are common.
  78. What are the changes in thyroid gland with Grave's disease that are induced by Iodine or PTU adminstartion?
    • Preoperative administration of iodine causes involution of the epithelium and the accumulation of colloid by blocking thyroglobulin secretion.
    • Treatment with propylthiouracil exaggerates the epithelial hypertrophy and hyperplasia by stimulating TSH secretion. 
  79. What are the changes in extrathroid tissue in Grave's disease?
    • 1. Generalized lymphoid hyperplasia.
    • 2. The heart may be hypertrophied, and ischemic changes may be present, particularly in patients with preexisting coronary artery disease.
    • 3. The tissues of the orbit are edematous because of the presence of hydrophilic mucopolysaccharides, lymphocytes and fibrosis
    • 4. The dermopathy is characterized by thickening of the dermis due to deposition of glycosaminoglycans and lymphocyte infiltration.
  80. Which of the Grave's manifestations might not respond to anti-thyroid  therapy?
    Ophthalmopathy
  81. What does Diffuse and multinodular goiters reflect?
    impaired synthesis of thyroid hormone, which is most often caused by dietary iodine deficiency.
  82. What is the cause of hypertrophy and hyperplasia of thyroid follicular cells and, ultimately, gross enlargement of the thyroid gland in goiter?
    TSH stimulation
  83. What is the underlying mechanism of nontoxic diffuse goiter?
    • Endemic goiter (>10% population) occurs in geographic areas where the soil, water, and food supply contain low levels of iodine. Variations in the prevalence of endemic goiter in regions with similar levels of iodine deficiency point to the existence of goitrogens such as cabbage, cauliflower, Brussels sprouts, turnips, and cassava. Cassava contains a thiocyanate that inhibits iodide transport. 
    • Sporadic goiter has a striking female preponderance. it can be caused by ingestion of goitrogens or dyshormonogenetic goiter.
  84. What are the two morphological phases of nontoxic diffuse goiter?
    The hyperplastic phase and the phase of colloid involution. In the hyperplastic phase, the thyroid gland is diffusely and symmetrically enlarged, the follicles are lined by crowded columnar cells, which may form projections similar to those seen in Graves disease. The accumulation is not uniform. If dietary iodine subsequently increases or if the demand for thyroid hormone decreases, the stimulated follicular epithelium involutes to form an enlarged, colloid-rich gland (colloid goiter). The follicular epithelium is flattened and cuboidal, and colloid is abundant during periods of involution.
  85. What is the main manifestation of diffuse nontoxic goiter?
    • Normal T3, T4
    • TSH ULN or elevated
    • Compression symptoms
  86. How does MNG form?
    • Recurrent episodes of hyperplasia and involution produce a irregular enlargement of the thyroid, termed multinodular goiter. Virtually all long-standing simple goiters convert into multinodular goiters. MNG produce the most extreme thyroid enlargements and are mistaken for neoplastic involvement.
    • MNG arise because of variations among follicular cells in their response to external stimuli. If some cells in a follicle have a growth advantage, perhaps because of intrinsic genetic abnormalities similar to those that give rise to adenomas, those cells can give rise to clones of proliferating cells (autonomous nodules)
    • Both polyclonal and monoclonal nodules coexist within the same multinodular goiter
    • Mutations affecting proteins of the TSH-signaling pathway that lead to constitutive activation is present in some autonomous thyroid nodules
  87. What is the morphological changes in MNG?
    • The uneven follicular hyperplasia, generation of new follicles, and uneven accumulation of colloid produce physical stress that leads to rupture of follicles and vessels followed by hemorrhages, scarring, and sometimes calcifications. With scarring, nodularity appears.
    • May become very large
    • Colloid-rich follicles lined by flattened, inactive epithelium and areas of follicular hyperplasia. In contrast to follicular neoplasms, a prominent capsule between the hyperplastic nodules and residual compressed thyroid parenchyma is not present 
  88. What are the clinical manifestations of MNG?
    • Mass effect (airway obstruction, dysphagia, and superior vena cava syndrome)--> MC. Most patients are euthyroid or have subclinical hyperthyroidism
    • Toxic multinodular goiter
    • Uneven iodine uptake
    • An admixture of hyperplastic and involuting nodules in multinodular goiter
  89. What are the alarming characteristics of a patient with thyroid lesion?
    • Male
    • Young
    • Single nodule
    • History of radiation
    • Nodules that are not hot
  90. What are the main DDx of follicular adenoma?
    Thyroid follicular cancer, follicular hyperplasia (MNG), or papillary cancer
  91. What are the genetic defects observed in follicular adenoma?
    • A minority of nonfunctioning follicular adenomas have mutations of RAS or phosphotidylinositol-3-kinase subunit (PIK3CA) or a PAX8-PPARG fusion gene --> shared with follicular carcinomas.
    • TSH receptor signaling pathway (Gain-of-function mutations in TSHR or the α-subunit of Gs (GNAS)—> associated with hot nodules in both >50 % toxic adenoma or MNG (not in carcinoma) 
  92. What is the hallmark of follicular adenoma in histology?
    It is encapsulated (unlike MNG)
  93. What are the morphological features of follicular adenoma?
    • Encapsulated
    • Monomorphic cells
    • Mitoses are rare
  94. What are the alarming histological features in follicular adenoma?
    Extensive mitotic activity, necrosis, or high cellularity warrants careful examination of the capsule to exclude a follicular carcinoma, as well as of the nuclear features to exclude a follicular variant of papillary carcinoma
  95. How can we distinguish follicular adenoma from other lesions?
    • Capsule from MNG
    • Intact capsule from follicular carcinoma
    • Nucleus from follicular variant of papillary cancer
  96. What are the disinguishing feature of Hurthle cell (oxyphil) adenoma?
    • cells acquire brightly eosinophilic granular cytoplasm
    • No difference in course from follicular adenoma
  97. What are the clinical features of follicular adenoma?
    • Painless mass
    • Mostly cold (reduced RAIU)
    • Must be resected to examine the capsule
  98. What is the mc thyroid cancer?
    PTC
  99. What are the two pathways involved in follicular derived thyroid cancers?
    the mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol-3-kinase (PI-3K)/AKT pathway
  100. What is the major genetic feature of PTC?
    • Activation of the MAP kinase by two mechanisms (thw two are mutually exclusive):
    • 1. rearrangements of RET or NTRK1 (neurotrophic tyrosine kinase receptor 1), both of which encode transmembrane receptor tyrosine kinases, 2. activating point mutations in BRAF (more aggressive), whose product is an intermediate signaling component in the MAP kinase pathway 
    • (RET/PTC rearrangements and BRAF point mutations are not observed in follicular adenomas or carcinomas)
  101. What is the genetic features of follicular carcinomas?
    • PI-3K/AKT (gain-of-function point mutations of RAS and PIK3CA, and loss-of-function mutations of PTEN)-->shared with follicular adenoma or anaplastic carcinoma
    • PAX8-PPARG fusion genes-unique
  102. What are the major environmental RF for thyroid cancer?
    • Ionizing radiation--> PTC
    • Iodine deficiency--> FTC
  103. What are the histological hallmarks of PTC?
    • 1. branching papillae having a fibrovascular stalk covered often by well-differentiated cuboidal cells. When present, the papillae of papillary carcinoma differ from those seen in areas of hyperplasia in being more complex and having dense fibrovascular cores.  
    • 2. finely dispersed chromatin, which imparts an optically clear or empty appearance, giving rise to the designation ground-glass or Orphan Annie eye nuclei. In addition, invaginations of the cytoplasm may in cross-sections give the appearance of intranuclear inclusions (“pseudo-inclusions”) or intranuclear grooves. The diagnosis of papillary carcinoma is made based on these nuclear features, even in the absence of papillary architecture.  
    • 3. Concentrically calcified structures termed psammoma bodies. These structures are almost never found in follicular and medullary carcinomas
    • 4. Foci of lymphatic invasion by tumor are often present, but involvement of blood vessels is relatively uncommon.
  104. What are the histological variants of PTC?
    • 1. follicular variant (mc), which has the characteristic nuclei of papillary carcinoma but has an almost totally follicular architecture. Less BRAF and RET/PTC but higher RAS, Less aggressive
    • 2. A tall-cell variant is marked by tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures. poorer prognosis, older age, higher BRAF, RET/PTC
    • 3. diffuse sclerosing: younger, papillary growth pattern, intermixed with solid areas containing nests of squamous metaplasia. extensive, diffuse fibrosis throughout the thyroid gland, often associated with a prominent lymphocytic infiltrate. Lymph node metastases in all cases. lack BRAF mutations
  105. What is the clinical course of PTC?
    • MC as asymptomatic thyroid nodules
    • Sometimes only LAP (no decline in prognosis)
    • Hoarseness, dysphagia, cough, or dyspnea suggests advanced disease. 
    • If hematogenous metastasis--> lung mc
    • Can be diagnosed with FNA
  106. How can FTC be distinguished from PTC?
    nuclei lack the features typical of papillary carcinoma, and psammoma bodies are not present.
  107. What are the clinical features of FTC?
    • Slowly enlarging painless nodules
    • Most frequently they are cold nodules
    • little propensity for invading lymphatics
    • vascular (hematogenous) dissemination is common
  108. What are the features of anaplastic thyroid cancer?
    • Older patients
    • Very aggressive (100% fatal)
    • History of previous thyroid cancer
    • Spindle cell and GC
    • Rapidly enlarging bulky neck mass
  109. What are two markers of MTC?
    Calcitonin, CEA
  110. Which thyroid cancer can cause paraneoplastic syndromes?
    ACTH, VIP, serotonin by MTC
  111. What is the main genetic abnormality in MTC?
    activating point mutations in the RET protooncogene
  112. What are the histological features of MTC?
    • Solitary nodule (sporadic), bilateral (hereditary)
    • Polygonal to spindle-shaped cells
    • Acellular amyloid deposits in the adjacent stroma in many cases
    • Membrane-bound electron-dense granules within the cytoplasm of the neoplastic cells in EM
    • Multicentric C-cell hyperplasia in familial cases
  113. What should be done in RET+ patients?
    Thyroidectomy (prophylactic)
  114. What is the poorest prognosis of MTC?
    MEN2B
  115. What is the mcc of poor prognosis in MEN?
    MTC

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