Thyroid Pathology PDF

Thyroid Pathology 1 Topics Laboratory and Radiologic Evaluation Disorders of development: Ectopia, Thyroglossal duct cyst, Aplasia Clinical Syndromes: Hyper and Hypo-thyroidism Euthyroid Sick Syndrome Graves disease Hashimotos thyroiditis Reidels thyroiditis Sub...

Thyroid Pathology 1 Topics Laboratory and Radiologic Evaluation Disorders of development: Ectopia, Thyroglossal duct cyst, Aplasia Clinical Syndromes: Hyper and Hypo-thyroidism Euthyroid Sick Syndrome Graves disease Hashimotos thyroiditis Reidels thyroiditis Subacute Thyroiditis Thyroid Tumors 2  Thyroid Evaluation Physical Examination Laboratory TSH T4 and T3: Free and Total Antibodies: anti-TPO (thyroid peroxidase) and anti-TSH receptor Thyroglobulin: Marker for Papillary Carcinoma and Follicular Carcinoma Calcitonin: Marker for Medullary Thyroid Carcinoma Fine needle aspiration/resection Imaging Ultrasound Thyroid 123I uptake scan 3  Thyroid Function Hypothalamus---TRH (Also stimulates Prolactin release) Induces iodination of tyrosyl Pituitary TSH residues of thyroglobulin (Tg) Proteolysis of Tg into T4 and T3 Tg brought into follicular cells and cleaved in phagolysosome to T4/T3 Deiodination of T4 into T3 Thyroid T4 T3 80% of T3 produced in periphery Circulating T4/T3 70% thyroxine binding rT3 T3 globulin 20% transthyretin 10% albumin 0.03% free T4 0.3% free T3 4  Thyroid Stimulating Hormone Pituitary hormone which stimulates production and release of thyroid hormones, T4 and T3 Has mildly diurnal pattern of release Has long half-life; mostly bound to circulating proteins Therefore has relatively stable serum levels Single measurement is adequate Responds to serum thyroid hormone levels High T4- - ->decreased TSH; Low T4- - ->increased TSH Usually done in conjunction with T4/T3, but TSH is single best test for thyroid function 5  T4 and T3 Two main ways to assess Total T4 and Total T3 Hormone bound to Thyroid Binding Globulin (TBG) Problem: TBG increases with estrogen, pregnancy, etc; decreases with cirrhosis, nephrosis etc. Total may be increased/decreased even though euthyroid Free T4 and Free T3 Unbound hormone which is physiologically active form Most will start with free T4/T3 6  I-123 Uptake Scan Nuclear medicine scan to assess thyroid metabolic activity Thyroid avidly takes iodine out of circulation Radioactive label allows visualization Gland contour Relative metabolic activity: Hot and Cold 7  I-123 Uptake Scan Nuclear medicine scan to assess thyroid metabolic activity 8  TSH and T4/T3 TSH is very sensitive to levels of T4/T3 Small changes in hormone cause large changes in TSH TSH alone is sometimes used as screening test TSH interpreted in light of T4/T3 If TSH abnormal, then get T4/T3 TSH is initial test of choice for hypo/hyperfunction What would pattern be if patient was hyperthyroid due to a primary thyroid disorder? TSH T4 T3 I-uptake 9  Fine Needle Aspiration Low morbidity procedure to assess thyroid nodule/mass Problem: 8% of US population has thyroid mass DDx: Cancer or Not cancer. 1-5% are cancer. Do we remove all nodules? Solution: FNA allows triage to two different buckets This might be malignant; High sensitivity; low predictive value This is not malignant; safe to leave in place Remove all “might be malignant” cases 10  Fine Needle Aspiration Aspiration material contains: Cells Follicular cells Papillary features Microfollicular features C-cells Normally too few to recognize Lymphocytes Benign or Malignant Others Colloid More colloid=more likely to be benign 11  Thyroid Developmental Disorders Thyroglossal duct path lies between foramen cecum to the pyramidal lobe of thyroid 12 Ectopic Thyroid May lie anywhere along thyroglossal duct path Ectopic thyroid is in DDx of mediastinal lingual, anterior neck masses DO NOT EXCISE lingual mass without knowing what it is! 13  Thyroglossal Duct Cyst Failure of duct involution Cystic remnants may persist anywhere along this path Sinus tracts to tongue may also be present Cysts are lined by squamous to follicular epithelium; filled with mucus and/or thyroid hormone Most 1-3 cm Classic location: Midline, above thyroid cartilage, below hyoid bone Prone to infection with URI Rarely develop malignancy 14  Hyperthyroidism Excess T4/T3 activity Review thyroid hormone actions Increase basal metabolic rate ↑ O2 consumption; ↑Heat production ↑ Heart Rate; ↑ Cardiac Output ↑ gut motility ↑bone turnover ↑gluconeogenesis and glycogenolysis ↑sensitivity to catecholamines- - ->alertness, sweating, heart rate 15  Hyperthyroidism Clinical Features 1-2% of women; 0.1-0.2% of men Increased basal metabolic rate Heat intolerance Weight loss Cardiac dysfunction Tachycardia and palpitations Arrhythmias, especially atrial fibrillation Congestive Heart Failure May be high output May be low output d/t LV dysfunction, especially elderly 16  Hyperthyroidism Clinical Features Sympathetic hyperfunction Hyperactivity, anxiety, tremor, insomnia Hyperhydrosis Hyperdefecation d/t increased gut motility Peripheral vasodilation Other Ocular-wide staring gaze with lid lag Skin: Warm and moist Skeletal-osteoporosis and increased fractures Fatty liver Muscle weakness/atrophy (Graves) 17  Hypothyroidism Clinical Features in adult Common, especially in woman (10x rate of men) Cool, dry skin, decreased sweating Thin, hyperkeratotic skin Thick, puffy appearance of eyes, hands/feet, shoulders Dermal glycosaminoglycans→non-pitting edema (AKA myxedema) Constipation Weight gain (modest, mostly due to myxedema) Cold intolerance Decreased cardiac contractility Decreased libido and fertility (remember TRH:Prl connection) 18  Hypothyroidism High index of suspicion is required! Common disorder Easily treatable DDx I’m tired I’m bored with life I’m overweight I’m pale 19 Hypothyroidism Laboratory Features Central Hypothyroidism 1% Low TSH; Low T4 T3 falls later in disease Primary Hypothyroidism 99% of cases High TSH; Low T4 20 21  Hyper/Hypothyroidism Most common causes of hyperthyroidism Graves Disease Toxic multinodular goiter Most common causes of hypothyroidism Hashimotos/autoimmune thyroiditis (>90%) Radiation injury Surgical removal Iodine deficiency Hypopituitarism (Subclinical hypothyroidism: 6-10% of population, especially elderly) 22  Hypothyroidism Clinical Features in neonate 1/4000 worldwide Greatly reduced in wealthy areas due to Iodine supplementation and neonatal screening Causes Maternal thyroid disease- - -> cretinism Supplies baby up to about 3-4 months GA Prenatal screening if personal or family history Also transplacental passage of autoantibodies Neonatal thyroid disease- - -> neonatal hypothyroidism Iodine deficiency (endemic goiter) Thyroid gland dysgenesis/agenesis Dyshormonogenesis TSH-R antibody mediated 23  Neonatal Hypothyroidism Effects Relatively normal at birth due to maternal hormone (if present) Large head and wide fontanels due to brain myxedema Prolonged jaundice Sluggish feeding, crying, general activity Umbilical hernia common Developmental, growth, and cognitive delays Features of adult hypothyroidism 24  Cretinism Intellectual disability due to intrauterine hypothyroidism (maternal) Cognitive delay and impairment Irreversible Growth impairment Umbilical hernia Protruding tongue Largely irradicated with universal newborn screening 25  Euthyroid Sick Syndrome Misleading laboratory results due to release of inflammatory mediators by systemically sick patients Decreased/altered binding proteins Decreased deiodination Altered TSH response : spuriously high or low May have: Low Total T3, Normal T4, Normal TSH Low TSH High TSH Low T4 and T3 Best solution is to test at recovery 26  Grave’s Disease Autoimmune disease caused by thyroid stimulating anti-TSH receptor antibodies Most common cause of hyperthyroidism Affects 1-2% of US women! Peak age 20-40yrs Women 10:1 27  Grave’s Disease Pathogenesis Autoantibodies against TSH receptor anti-TSH-R: Thyroid stimulating antibodies induce signal transduction Release of T4, T3 Diffuse thyroid hyperplasia TSH receptors in orbital fat and pretibial connective tissue TBII: Thyroid Binding Inhibitory Immunoglobulins present in minority Block binding site- - ->hypothyroidism 28  Grave’s Disease Clinical Hyperthyroidism in 90-95% Graves Ophthalmopathy in 35% Graves Dermopathy: Pretibial Myxedema in 5% Most common to have Hyperthyroid with orbital/derm change later May be independent Euthyroid + GO Hypothyroid + GO Hypothyroid alone Etc 29  Grave’s Disease Ophthalmopathy All hyperthyroidism shows wide gaze with lid lag Due to sympathetic overactivity Graves includes expansion of orbital fat - - -> Proptosis AKA exophthalmos May interfere with extraocular muscles, lid closure May- - ->diplopia, blurry vision, motion limitation May be seen in patients with anti-TSH but no hyperthyroidism May continue after gland removed 30  Grave’s Disease Dermopathy in 5% Well-defined myxedematous plagues on pre-tibial skin Glycosaminoglycan deposition Non-pitting 31  Grave’s Disease Morphology Diffuse symmetric gland enlargement Follicular cells stimulated- - ->Tall plump cells Colloid consumed- - ->small follicles Colloid consumed- - ->colloid scalloped Immune reaction- - ->Lymphocytes 32 Grave’s Disease Normal Graves 33  Graves Disease Let’s Predict the Lab Studies!!! Treatment T4/T3 Propylthiouracil TSH Ablation I-uptake Surgery Serology 34  Hashimoto Thyroiditis Autoimmune destruction of thyroid gland 90% of hypothyroidism in regions of sufficient iodine Peak Age 40-60yrs Incidence 4/1000 women; 1/1000 men 35  Hashimoto Thyroiditis Pathogenesis T-cell-mediated immune destruction of gland Circulating autoantibodies are often present also Anti-TSH (blocking usually) Anti-TPO** Anti-thyroglobulin** **may be elevated in any form of immune destruction of thyroid Immune destruction of gland Cell apoptosis May have initial hormone release - - ->transient hyperthyroidism Gradual gland shrinkage and fibrosis- - ->symmetrically small fibrotic gland 36  Hashimoto Thyroiditis Clinical Early Chronic inflammation Gland is enlarged, non-tender, firm May be hyperthyroid, eu-, or hypothyroid Late Follicle destruction Slow decrease in gland size +/- nodularity Capsule remains intact; gland mobile Hypothyroid 37  Hashimoto Thyroiditis Clinical Increased risk of other autoimmune diseases Diabetes Vitiligo Pernicious Anemia Myasthenia gravis Continued immune stimulation Increased risk of MALToma Official Name: 38  Hashimoto Thyroiditis Cell-mediated immune destruction of follicular epithelial cells Chronic inflammation……………………Fibrosis Hypothyroid Euthyroid Transient Hyperthyroid 39  Hashimoto Thyroiditis Morphology Early on may have gland enlargement Brisk lymphocytic inflammation Germinal centers Thyroid epithelium- - ->Hurthle cell metaplasia (big and pink) Eventual gland atrophy Eventual gland fibrosis 40  Hashimoto Thyroiditis Morphology TIME 41  Hashimoto Thyroiditis Diagnosis Early possibility: High T4/T3, Low TSH BUT Decreased thyroid uptake Primary hypothyroidism (if late enough) TSH: T4/T3: Serology Anti-TPO Anti-thyroglobulin Anti-TSH blocking Thyroid Iodine Scan Decreased uptake Shrunken; May show nodularity 42  Reidels Thyroiditis Fibrosing disease of thyroid Rare Mostly middle age women May be a form of IgG4 disease 43  Reidels Thyroiditis Clinical Slowly developing hypothyroidism Most prominent: symptoms of compression Trachea, nerves, vessels Painless** Fibrosis- - ->Rock hard gland Asymmetric, fixed in place DDx: Cancer with invasion of adjacent structures 44  Subacute Thyroiditis Viral thyroiditis AKA deQuervain Thyroiditis; Granulomatous Thyroiditis Usually follows URI with variable viruses (mumps, coxsackie, adeno..) Then viral infection of thyroid Follicular cell apoptosis and release of colloid- - ->Giant cells and granulomatous response 45  Subacute Thyroiditis Clinical Follows URI Then Painful thyroid on swallowing, neck motion, etc Patient is hyperthyroid Then Hypothyroid as gland is depleted Then restored to normal CRP/ESR usually elevated I-scan decreased uptake 46 Subacute Thyroiditis FTI: Free thyroxine Tg: thyroglobulin TSH: TSH 47 Subacute Thyroiditis Morphology Follicle depletion and rupture Granulomatous reaction 48  Subacute Painless Thyroiditis Lymphocytic thyroiditis without Hurthle Cells or Germinal Centers Usually self-limited Usually women, often post-partum Transient hyperthyroidism, then normalizes Morphology Similar to Hashimotos but no Hurthle Cells Clinical Similar to Subacute Granulomatous but lymphocytes, not granulomas Autoimmune not viral ESR/CRP normal; I-scan with decreased uptake 49  Goiter Term for thyroid enlargement Includes some of today’s defined entities Also due to intact feedback loops Hypothyroidism- - ->high TSH- - ->gland hyperplasia- - ->(hopefully euthyroid) Causes Iodine Deficiency: (Endemic Goiter): Common worldwide (mountain, inland) Inborn errors- - ->Dyshormonogenetic Goiter Goitrogens: Dietary inhibitors of T4/T3 synthesis Broccoli, Cauliflower, Kale, Brussels Sprouts, Cabbage, soy, others Lithium Sporadic: Unknown cause; usually young women 50  Endemic Goiter Geographic regions with >10% Iodine Deficient goiter People usually euthyroid Symmetric diffuse gland enlargement Usually modest enlargement Typical labs Normal T4, High TSH or High Normal TSH Gradually form areas of involution - - -> “Colloid Goiter” Zones of HIGH colloid content 51  Multinodular Goiter Evolution of multinodularity out of diffuse goiter May arise in Endemic or Sporadic goiters, etc Late complication so older age group May produce huge glands May produce hyperfunctioning nodules “Toxic Nodule” or “Hot Nodule” 52  Multinodular Goiter Diffuse Non-toxic Pathogenesis Goiter Compensatory hypertrophy and hyperplasia Dietary Iodine deficiency, Goitrogen, Sporadic TSH response- - -> Euthyroid state Severe deficiency may lead to goitrous hypothyroidism Initial response results in diffuse enlargement Multinodular Goiter 53  Multinodular Goiter Diffuse Non-toxic Pathogenesis Goiter Compensatory hypertrophy and hyperplasia Dietary Iodine deficiency, Goitrogen, Sporadic TSH response- - -> Euthyroid state Severe deficiency may lead to goitrous hypothyroidism Initial response results in diffuse enlargement Over time, areas of involution develop Other areas become hyperplastic Multinodular Goiter 54  Multinodular Goiter Pathogenesis Diffuse Non-toxic Goiter Compensatory hypertrophy and hyperplasia Dietary Iodine deficiency, Goitrogen, Sporadic TSH response- - -> Euthyroid state Severe deficiency may lead to goitrous hypothyroidism Initial response results in diffuse enlargement Over time, areas of involution develop Other areas become hyperplastic Development of zones of clonality Areas of proliferation Areas of involution- - ->cold nodules (Toxic) May become autonomous T4 producers- - ->Toxic or “hot” nodule) Multinodular Goiter 55  Multinodular Goiter Morphology Labs: T4: TSH: Thyroid Scan: 56 Multinodular Goiter 57  Multinodular Goiter Clinical Usually euthyroid, may have subclinical hypothyroidism May have hyperthyroidism Symptoms Cosmetic Mass effect and compression Vascular Airway SVC syndrome 58  Goiter Terminology Diffuse Nontoxic Goiter Multinodular Goiter Toxic Multinodular Goiter “hot” nodule “cold” nodule 59  Thyroid Tumors Benign Hyperplastic Nodule/Multinodular Goiter Follicular Adenoma Malignant Papillary Thyroid Carcinoma Follicular Carcinoma Medullary Carcinoma Insular Carcinoma Anaplastic Carcinoma 60  Thyroid Nodules General Up to 8% of US population has a thyroid nodule >Males Age Peak: 40-50yrs Mostly incidental findings on physical or imaging 63  Follicular Adenoma Clinical Most are non-functioning, “cold” nodules Non-functioning, cold nodules Incidental findings Minority show constitutive activation of TSH signaling pathway Toxic and hot TSH receptor mutations G-protein α subunit mutations 64  Follicular Adenoma Morphology Encapsulated Well circumscribed NO capsular penetration NO vascular invasion Small caliber follicles, “microfollicles” DDx in FNA: follicular carcinoma Must be removed for diagnosis Surgery is curative 65 Follicular Adenoma 66  Follicular Adenoma Fine Needle Aspirate findings 67  Thyroid Cancer Features Common: Incidence 50,000/yr in US 98% 5 yr survival Types Papillary Carcinoma 80% Very low grade Follicular Carcinoma 10% Poorly differentiated or Anaplastic 5% Medullary Carcinoma 5% Risk factors Ionizing radiation as youth: especially for Papillary and Follicular Family history, especially for Medullary 68  Thyroid Cancer Genetics Papillary Translocation: RET-PTC or NTRK gene fusions Activating Point mutations: BRAFv600e- - ->worse prognosis Follicular RAS or PIK3 gain of function PTEN loss of function PPARG-Pax8 fusion gene Poorly Differentiation/Anaplastic Arise from PTC, FTC Same mutations with addition of p53, β-catenin, and/or TERT Medullary RET oncogenes 69  Papillary Carcinoma Malignant neoplasm of follicular epithelial cells with papillary morphology (cytologic or architectural) 80+% of thyroid cancers 25-50 years Tend to be cold nodules Associated with radiation exposure Dissemination is through lymphatic route Prognosis >95% 10 year survival 70  Papillary Carcinoma Morphology Nuclear features Longitudinal grooves INCI’s Ground glass nuclei Architecture Papillae with fibrovascular cores Psammoma bodies 71 Papillary Carcinoma 72 Papillary Carcinoma 73 Papillary Carcinoma 74 Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features NIFT-P Putative benign precursor to Follicular vt. Papillary Carcinoma Follicular type mutations V600E May have BRAF, but not BRAF Needs strict histologic criteria to have benign prognosis Complete encapsulation No vascular or capsular invasion No necrosis Rare mitoses (90% 10 year survival Minimally invasive: 50% 10 year survival 76  Follicular Carcinoma Morphology Malignant neoplasm of follicular epithelial cell Often surrounded by a fibrous capsule Cells and architecture same as follicular adenoma Defined by capsular and/or vascular invasion Minimally invasive if 4 vessels or extensive invasion of thyroid and soft tissues 77 Follicular Carcinoma 78  Follicular Carcinoma FNA cytology of follicular carcinoma What do you notice?? 79  Poorly/Undifferentiated Carcinoma High grade malignant neoplasms of follicular epithelium Most likely arise from pre-existing papillary or follicular carcinoma Same demographics but older Addition of p53 inactivation or β-catenin activation Approaching 100% 1 year mortality PD carcinoma slightly better 80  Poorly/Undifferentiated Carcinoma Clinical Rapidly enlarging, bulky masses Elderly patients, often with long-term goiter Tend to be locally invasive and unresectable Symptoms from invasion, compression of local structures Hoarseness, stridor, dysphagia, nerve dysfunction 81  Poorly/Undifferentiated Carcinoma Clinical 82  Poorly/Undifferentiated Carcinoma Morphology Highly variable Spindled/sarcomatoid Spindled and giant cells Sheets of malignant epithelial cells Some with recognizable areas of residual Papillary or Follicular Carcinoma 83 Poorly/Undifferentiated Carcinoma 84  Medullary Carcinoma Malignant neoplasm of thyroid C-cells Neuroendocrine cells which secrete calcitonin Arise in two settings Sporadic Familial (MEN-2a and MEN-2b syndromes) 85  Medullary Carcinoma Malignant neuroendocrine neoplasm of C-cells ~5% of thyroid malignancies Sporadic (70%) Familial 40-50 year old Teens and 20’s Single mass Often multiple No surrounding C-cell C-cell hyperplasia hyperplasia 86  Medullary Carcinoma Clinical Secrete calcitonin Normal calcium levels usually Used diagnostically and for follow-up Symptoms from mass effect Sometimes secretes VIP and/or ACTH Diarrhea Cushings syndrome Prognosis Highly stage dependent 100% survival if limited to thyroid; overall 50% 5 year survival Treatment Surgery Prophylactic surgery if syndromic 87  Medullary Carcinoma Morphology Spindled and epithelioid cells Calcitonin Positive*** Produce amyloid frequently*** 88 Medullary Carcinoma 89 Medullary Carcinoma Amyloid Positive 90 91