Thyroid

Question 1

What are follicles lined by?

Answer 1

cuboidal to low columnar follicular cells

Question 2

What do parafollicular or C cells secrete? What origin ar they?

Answer 2

calcitonin-promotes absorption of calcium by the skeletal system and inhibits reabsorption of bone
Neural crest origin

Question 3

What is the mechanism of action and function of thyroid hormones?

Answer 3

1. Stimulation of protein synthesis
2. Up regulation of carbohydrates and lipid catabolism
3. Increase in basal metabolic rate
4. critical role in the development of brain in fetuses and neonates

Question 4

Thyrotoxicosis

Answer 4

Hyper metabolic state due to increased circulating levels of thyroid hormones (T4 and T3)
-most commonly caused by hyper functioning of the thyroid gland but can be not associated with hyperthyroidism

Question 5

Clinical manifestations of hyperthyroidism/ thyrotoxicosis

Answer 5

Excess thyroid hormone and over activity of sympathetic nervous system

1. Increased BMR-soft warm flushed skin
2. Heat intolerance and excess sweating
3. Weight loss despite increased appetite
4. Cardiovascular-increased CO, tachy, palpitaitons, cardiomegaly, arrhythmias especially atrial fibrillation is common in the elderly
5. Development of low output heart failure
6. Neuromuscular-nervousness, emotional lability, insomnia, muscular weakness, fine tremor of the hands
7. proximal muscle weakness and decreased muscle mass
8. Gastrointestinal: hypermotility, malabsorption
9. Wide staring gaze and lid lag
10. Thyroid ophthalmopathy (proptosis) only associated with graves
11. Stimulates bone resorption and osteoporosis
12. THyroid storm-medical emergency

Question 6

Diagnosis of hyperthyroidism

Answer 6

TSH levels-usually decreased-Most sensitive

Free T4-usually increased

Question 7

How do you exclude secondary or pituitary associated hyperthyroidism?

Answer 7

TRH stimulation test

• inject TRH
• if normal rise in TSH then it is not secondary hyperthyroidism

Question 8

What radioactive iodine uptake results indicate Graves, toxic adenoma, or thyroiditis?

Answer 8

graves: diffuse uptake
toxic adenoma: localized
thyroiditis: reduced uptake

Question 9

What is the most common cause of hypothyroidism?

Answer 9

primary hypothyroidism

-can be accompanied by enlargement of the gland(goiter)

Question 10

What is the most common worldwide congenital hypothyroidism due to?

Answer 10

iodine deficiency

Question 11

Cretinism

Answer 11

Hypothyroidism in infants or early childhood

• secondary to iodine deficiency or rarely from inborn errors in metabolism
• impaired development of skeletal muscles and CNS: severity varies to timing of deficiency
• if maternal thyroid hormone deficiency before development of fetal thyroid, mental retardation is sever
• mental retardation, short stature, coarse facial features

Question 12

Hypothyroidism Myxedema

Answer 12

Adult hypothyroidism
Gradual slowing of mental and physical activity
-fatigue, lethargy, apathy, slowed speech
-cold intolerance and reduced sweating
-overweight and constipation
-periorbital edema, thick coarse skin, enlarged tongue (deposition of glycosaminoglycans)
-reduced cardiac output causes shortness of breath and decreased exercise capacity
-promotes an atherogenic profile (increased cholesterol)-adverse cardiovascular mortalities

Question 13

What lab values do you find in hypothyroidism?

Answer 13

Decreased T4
TSH levels-most sensitive for hypothyroidism
Primary-Increased TSH
Secondary-Decreased/normal TSH

Question 14

Thyroiditis

types with Pain and No pain

Answer 14

1. Inflammation with pain, sometimes severe
   - Infectious thyroiditis
   - subacute granulomatous thyroiditis (De quervain thyroiditis)
2. Relatively little pain
   - Subacute lymphocytic thyroiditis
   - Riedel’s thyroiditis
   - Hashimoto’s thyroiditis

Question 15

Hashimoto Thyroiditis

Answer 15

most common hypothyroidism in non-iodine deficient areas

• autoimmune destruction of thyroid gland
• 45-65
• major cause of non endemic goiter in pediatric age group
• strong genetic component

Question 16

What are the three mechanisms of breakdown in self tolerance and induction of thyroid autoimmunity in Hash?

Answer 16

1. T cell mediated cytotoxicity-CD8
2. Thyrocyte injury-CD4-INF gamma-macrophages
3. Antibody-dependent cell mediated cytotoxicity

Question 17

What antibodies are seen in hashimoto thyroiditis?

Answer 17

1. Thyroglobulin and thyroid peroxidase (TPO)!!!
2. TSH receptor
3. Iodine receptor

Question 18

Hashimoto thyroiditis
Gross
Histology

Answer 18

Gross
Diffusely enlarged gland 
Intact Capsule 
Well demarcated 
Pale, yellow, tan and somewhat nodular and firm

Histology:

1. Thyroid follicles lined by Hurthle cells/oncocytes
   - have abundant granular pink cytoplasm (numerous mitochondria)
2. formation of germinal centers
3. Thyroid parenchyma infiltrated by mononuclear inflammatory cells
   - blue lymphocytes
   - pink cells forming a follicle with colloid in the middle-residual follicular cells

Question 19

Clinical course Hashimoto Thyroiditis

Answer 19

• transient hyperthyroidism due to disruption of thyroid follicles with release of thyroid hormones (hashitoxicosis)
• gradual hypothyroidism
• increased risk of developing other autoimmune
• increased risk of developing Non Hodgkin B cell lymphoma

Question 20

Subacute/Granulomatous (de quervain) thyroiditis

Answer 20

40-50 years of age

• viral or post-viral inflammatory response
• viral antigens or virus induced host tissue damage stimulates formation of cytotoxic T cells which then damage the thyroid follicular cells (process is self limited)
• Most Common cause of thyroid pain
• variable enlargement of thyroid
• history of upper respiratory infection
• transient hyperthyroidism–hypothyroidism–euthyroid
• hyperthyroid phase: T3, T4, decreased TSH, radioactive iodine is diminished
• recovery and normal thyroid function in 6-8 weeks

Question 21

Subacute/Granulomatous (de quervain) thyroiditis

histology

Answer 21

1. unilateral or bilateral enlarged firm with intact capsule
2. changes are patchy
   3.
   early stage-disruption of follicles with collections of neutrophils forming microabscesses
   later stage-aggregates of lymphocytes, plasma cells and activated macrophages around damaged thyroid follicles
   -multinucleated giant cells of enclosed fragments of colloid
3. eventually chronic inflammation and fibrosis

Question 22

Riedel thyroiditis

Answer 22

rare disorder of unknown etiology

• extensive fibrosis involving the thyroid and contiguous neck structures
• hard and fixed mass-clinically simulating cancer**
• may be associated with idiopathic fibrosis at other sites like retroperitoneum
• presence of circulating antibodies- autoimmune etiology

Question 23

Graves Disease

Answer 23

Most common cause of hyperthyroidism

1. Hyperthyroidism due to diffuse hyperfunctional enlargement of thyroid
2. infiltrative opthalmo exophthalmo-accumulation of loose connective tissue behind eyeballs-weak extraocular muscles
3. infiltrative dermopathy pretibial myxedema (present in minority of patients)

• 20-40 yrs
• 30-40% concordance in monozygotic twins as compared to 5% in di

Question 24

What are the autoantibodies seen in graves disease

Answer 24

1. Thyroid stimulating immunoglobulin (TSI)-binds to TSH receptor and mimics its actions (specific for graves)
2. Thyroid growth stimulating immunoglobulin-cause(TGI) proliferation of follicular epithelium
3. TSH-binding inhibitor immunoglobulin (TBII)

Question 25

What does graves look like grossly and histologically

Answer 25

Gross symmetrically enlarged glands weigh may be >80 g soft meaty appearance of the parenchyma Histological: Crowded and tall follicular cells Formation of small papillae filling the lumen of the follicles Papillae do NOT contain fibrovascular cords Pale colloid with scalloped margins -lymphoid infiltrate with germinal centers common

Question 26

What lab findings do you see with graves disease?

Answer 26

Increased serum levels of thyroid hormones Decreased TSH Increased radioactive iodine uptake with diffuse uptake on radioiodine scans

Question 27

What are the treatments to graves disease?

Answer 27

1. Beta Blockers- symptomatic treatment of increased adrenergic tone (tachy, palp, tremulousness, anxiety) 2. Propylthiouracil: decreased thyroid hormone synthesis 3. radioiodine ablation 4. surgery

Question 28

Diffuse/ Nontoxic simple goiter Gross HIsto CLinical

Answer 28

Enlargement of the entire glad without producing nodularity Diffuse symmetric enlargement Gross 100-150 gm cut surface-brown, glassy and translucent Histologically: 2 phases 1. hyperplastic phage-enlarged thyroid gland with crowded follicular cells 2. colloid involution - some follicles are distended and some are small -entire gland shows flattened epithelium and follicles filled with colloid Clinical course - vast majority euthyroid - mass effect-large thyroid my press on trachea, esophagus and cosmetic disfigurement - Normal T4 and T3 - Elevated TSH or in the upper limit of normal

Question 29

Multinodular Goiter Gross Histology Clinical

Answer 29

Asymmetric enlargement with numerous nodules - evolvement from diffuse due to repeated episodes of hyperplasia and involution - older adults - both polyclonal and monoclonal nodules occur within the same gland - toxic or non toxic ``` Gross Asymmetric multilobulated 200 gm irregular nodules containing gelatinous colloid foci of fibrosis and calcification ``` Histology Colloid rich follicles lined by flattened inactive epithelium -areas of follicular hyperplasia DO NOT have a prominent capsule between the hyperplastic nodule and adjacent parenchyma

Question 30

Multinodular Goiter clinical features? How do you tell if the mass is benign or malignant

Answer 30

- Mass effect with disfigurement or compression - most patients euthyroid -minority develop toxic due to development of - autonomous nodule (plummer's syndrome) risk of malignancy

Question 31

Nodules more likely to be neoplastic in:

Answer 31

``` 90% 20 year survival More likely to neoplastic: -single nodule -young patients -male patients -nonfunctioning "cold" nodule -history of radiation to the head the neck ```

Question 32

Follicular Adenoma Mutation Gross Histology

Answer 32

Discrete solitary masses derived from follicular epithelium Mutation: RAS or PAX8-PPARG fusion gene -similar to mutations seen in follicular carcinomas Gross: solitary, ENCAPSULATED, spherical mass -well demarcated, 3cm -gray-white to red brown mass -may have areas of hemorrhage, necrosis or calcification Histology: neoplastic cells arranged in closely packed follicles -well defined intact capsule (distinguish from hyperplastic nodules of multinodular goiter) -uniform small follicles hurthle cell/oxyphilic/oncocytic adenoma

Question 33

Follicular Adenoma | Clinical features

Answer 33

- Capsule well defined and intact - NEED ENTIRE NODULE FOR DIAGNOSIS *** ``` Painless asymptomatic mass cold on radioactive iodine scan rarely functioning toxic adenoma treatment lobectomy excellent prognosis-do not recur or metastasize ```

Question 34

Are males or females more likely to get carcinomas of the thyroid in middle adulthood, what about in childhood and late adult life? What type of carcinoma is most common?

Answer 34

>F early middle adult M=F childhood and late adult life Papillary carcinoma

Question 35

Papillary Carcinoma

Answer 35

commonly 25-50yrs majority associated with radiation exposure ``` gross: solitary or multifocal lesion -may be well circumscribed and encapsulated or may be ill defined and infiltrative -papillary structures -foci of fibrosis and calcification ``` Histology: Branching papillae with fibrovascular cores lined by multiple layers of cuboidal to columnar epithelium **Diagnosis based on nuclear features -longitudinal nuclear grooves -ground glass or orphan annie eyed nuclei -psammoma bodies-calcified lamellar concretions usually seen in the cores of the papillae

Question 36

Variants of Papillary carcinoma

Answer 36

1. Follicular variant-based on nuclear features-frequently encapsulated, lower incidence of lymph node and extrathyroidal metastasis and favorable prognosis (no papillae seen) 2. Tall variant-tall columnar cells with intense eosinophilic cytoplasm lining the papillary structures, aggressive behavior 3. Diffuse sclerosis-younger individuals including kids 4. Papillary microcarcinomas-less than 1cm

Question 37

Papillary Carcinoma clinical features

Answer 37

- May be asymptomatic nodule or lymph node metastasis - cold Diagnose: diagnosed by fine needle aspiration cytology Treat: Total thyroidectomy with excision of abnormal appearing lymph nodes Good prognosis>95% ten-year survival prognosis dependent on: >40 less favorable, extrathyroid extension and distant metastasis (stage), isolated cervical lymph node met does not have effect on prognosis

Question 38

Papillary carcinoma genetic events

Answer 38

1. Rearrangement of RET 10q11 with RET/PTC translocation 20-40% 2. Paracentric inversions or translocations of NTRK1 5-10% 3. BRAF gene-adverse prognostic factors 33-50%

Question 39

Follicular Carcinoma

Answer 39

Second most common thyroid cancer older age 40-60 Higher incidence in iodine deficient area -minimally invasive or widely invasive Gross: -single well circumscribed nodule largely replacing almost the entire lobe -nodule has light tan appearance and contain foci of hemorrhage (may be difficult to distinguish from follicular adenomas grossly) -may extend beyond capsule to involve adjacent neck structures Histology: lacks typical nuclear features of papillary carcinoma -vascular invasion and/or capsular invasion

Question 40

Follicular Carcinoma clinical course/genetics

Answer 40

- Slowly growing painless nodule - cold - hematogenous met to bone, lung, liver Treatment: total thyroidectomy with radioactive iodine Prognosis dependent on metastasis Genetics: 1/3 to 1/2 PI3K/AKT pathway 1/3 to 1/2 have translocation (2;3)(q13;p25) resulting in PAX8/PPARG fusion product

Question 41

Medullary Carcinoma

Answer 41

Neuroendocrine neoplasm derived from the parafollicular or C cells - may secrete calcitonin or ACTH or VIP - 70 % sporadic (single), 30% familial or associated with MEN2A or 2B (multiple) - MEN: first decade - Familial or sporadic: 4 or 5th decade Gross: solid grey tan tumor with NO well defined capsule with infiltration of adjacent thyroid parenchyma -larger lesions with foci of hemorrhage and necrosis Histological: polygonal to spindle shaped cells forming nests, trabeculae and follicles AMYLOID deposits from calcitonin

Question 42

Medullary carcinoma clinical course

Answer 42

- May be mass or asymptomatic - may present with paraneoplastic syndrome VIP (diarrhea) and ACTH (cushing) - MEN2B more aggressive - hypocalcemia not prominent despite calcitonin Treatment total thyroidectomy MEN-3 with RET mutation are offered prophylactic thyroidectomy as early as possible

Question 43

Anaplastic carcinoma

Answer 43

undifferentiated tumors accounting for 5% 65 years old mortality approaches 100% with most patients dying in less than 1 year histology: highly anaplastic cells, spindles, giant cells - foci or papillary differentiation may suggest their origin from better differentiated tumor Clinically: presents as rapidly enlarging bulky mass -usually spread -dyspnea, dysphagia, hoarseness and cough de to compression of neck structures no effective therapy Genetic: inactivation of p53 or activating mutations of beta catenin

Question 44

Thyroglossal duct/cyst

Answer 44

incomplete atrophy o f the duct - midline cyst or anterior mass - lined by benign epithelium with normal thyroid and lymphocytes in the wall - infection with risk of abscess formation